Autosomal Dominant Nonsyndromic Hearing Loss 41

Mendelian MONDO:0011994 Pathograph 13 Show in embeddings browser Autosomal Dominant Nonsyndromic Hearing Loss

DFNA41 is autosomal dominant progressive sensorineural hearing loss associated with heterozygous P2RX2 variants. The best-supported alleles include p.Val60Leu and p.Gly353Arg. Age at recognition varies across families and publications; childhood/adolescent presentations preclude treating it as exclusively adult-onset. Occupational noise exposure was associated with poorer high-frequency hearing among p.Val60Leu carriers. Hyperalgesia was reported in one additional family, and a profoundly deaf proband benefited from cochlear implantation. P2X2 is an ATP-gated cation channel. The functional defect is allele- and assay-dependent: p.Val60Leu has markedly impaired ATP-evoked responses, with constitutive activity in a 2019 study but small ATP-triggered currents and reduced cell viability in a 2025 study. p.Gly353Arg retains channel activity with altered ATP sensitivity, rectification and ion selectivity. A universal dominant-negative mechanism is not established. P2rx2-null mice demonstrate a protective purinergic component of adaptation to sustained sound; this does not mean all temporary threshold shifts are harmless. The connection between specific human channel defects, adaptation and progressive cochlear injury remains incompletely resolved. Allele-selective genome editing preserved hearing at selected frequencies and reduced noise susceptibility in heterozygous p.Val61Leu mice, the mouse counterpart of human p.Val60Leu. This is preclinical evidence, supplemented by editing in human patient-derived cells. ClinGen's September 2022 gene-disease classification remains Moderate in the reviewed assertion; variant-specific interpretation is essential.

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Inheritance
3
Pathophys.
4
Phenotypes
1
Hypotheses
3
Gaps
13
Pathograph
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Genes
5
Medical Actions
6
Models
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References
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Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous disease-causing P2RX2 variants segregate with dominant hearing loss. Full penetrance was reported in the original p.Val60Leu index pedigree; it is not established for every P2RX2 variant. A heterozygous affected parent has a 50% probability of transmitting the variant per pregnancy, independently of the severity or timing of expression.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in..."
Dominant segregation and full penetrance in the index family; the second family supplies additional segregation evidence.
PMID:24211385 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus."
Independent linkage evidence for dominant inheritance at the same locus.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child."
Mendelian transmission probability after establishing a causal dominant allele; not a universal penetrance estimate.
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Mechanistic Hypotheses

1
dfna41_channel_to_cochlear_injury
dfna41_channel_to_cochlear_injury
Allele-specific channel abnormalities may impair cochlear adaptation and contribute to cellular/synaptic injury. Null-mouse adaptation physiology and heterozygous knock-in pathology support this proposal, but the complete causal route has not been established in human carriers.
Pathograph links
Variant-Specific P2X2 Channel Dysfunction -> Loss of Purinergic Adaptation to Elevated Sound Levels INDIRECT UNKNOWN INTERMEDIATES Inferred tissue consequence of allele-specific channel dysfunction; not directly established by heterologous-cell assays.
Variant-Specific P2X2 Channel Dysfunction -> Inner Hair Cell and Ribbon Synapse Disorganisation INDIRECT UNKNOWN INTERMEDIATES Inferred tissue consequence of allele-specific channel dysfunction; not directly established by heterologous-cell assays.
Loss of Purinergic Adaptation to Elevated Sound Levels -> Inner Hair Cell and Ribbon Synapse Disorganisation INDIRECT UNKNOWN INTERMEDIATES Supported by mouse noise-susceptibility experiments, with the contribution in human variant carriers still inferred.
Loss of Purinergic Adaptation to Elevated Sound Levels -> Noise-Exacerbated High-Frequency Hearing Impairment INDIRECT UNKNOWN INTERMEDIATES Supported by mouse noise-susceptibility experiments, with the contribution in human variant carriers still inferred.
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Discussions and Knowledge Gaps

3
How much noise is too much for a P2RX2 carrier? Is there a dose below which a carrier is no worse off than a non-carrier, and does hearing conservation started before onset change the trajectory?
KNOWLEDGE GAP dfna41_carrier_noise_dose_response
Attached to
environmental#Occupational and recreational noise exposure treatments#Hearing Conservation and Noise Avoidance phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
Human evidence relates recalled occupational exposure to hearing thresholds. Mouse experiments establish protocol-specific susceptibility but do not define a safe human carrier dose or show the benefit of a conservation program. A longitudinal cohort with dosimetry, audiometry and genotype-negative relatives could quantify the interaction.
Proposed experiments
Longitudinal noise dosimetry in P2RX2 carriers and non-carrier relatives
exp_dfna41_carrier_noise_dosimetry_cohort
Enrol carriers and genotype-negative relatives from known DFNA41 kindreds, measure cumulative noise exposure by personal dosimetry rather than by questionnaire, and follow pure tone and extended high-frequency audiometry annually. Model threshold change against cumulative dose separately by genotype to estimate whether the exposure-response curve is shifted and by how much.
Would support
phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
Would refute
phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
Supporting outcome
  • Carriers show a steeper threshold-versus-dose slope than non-carrier relatives, with separation beginning at exposures within current occupational limits, which would justify genotype-specific exposure advice and give a number to give patients.
Refuting outcome
  • No association between measured exposure and excess carrier decline would weaken a genotype-specific exposure-response claim; general hearing-conservation advice would still apply.
Show evidence (1 reference)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
Observational association motivates, but does not answer, the prospective exposure-response question.
How do allele-specific channel changes in heterozygous carriers affect purinergic adaptation, and which mechanisms explain progressive loss?
HUMAN MODEL MISMATCH dfna41_null_versus_heterozygous_mechanism
Attached to
pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels animal_models#P2rx2 null mouse
Null-mouse physiology establishes an adaptive P2X2 pathway. Dominant missense disease is not equivalent to partial gene deletion: heterozygous null mice retained adaptation, p.Val60Leu shows assay-dependent gating abnormalities, and dominant-negative effects on wild-type P2X2 are contested. Editing improves noise-susceptibility endpoints without directly testing temporary-threshold adaptation.
Proposed experiments
Temporary threshold adaptation in P2rx2 V61L heterozygous mice
exp_dfna41_tts_in_heterozygous_knockin
Compare genotype-matched and background-matched knock-in, null, heterozygous-null and wild-type mice using baseline-adjusted ABR/DPOAE noise protocols and ATP-evoked cochlear measurements. Include edited knock-in ears to test whether endpoint rescue accompanies restoration of purinergic adaptation.
Would support
pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
Would refute
pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
Supporting outcome
  • Reduced adaptation in knock-in mice, accompanied by correction after editing, would support the proposed link between allele dysfunction and loss of noise protection.
Refuting outcome
  • Normal adaptation despite progressive knock-in hearing loss would argue against this being the sole disease mechanism.
Show evidence (4 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645545/ SUPPORT DIRECT PRIMARY RESULT Model Organism
"These data indicate haplosufficiency in the development of P2X ... receptor-dependent TTS."
Heterozygous null mice retained adaptation, preventing direct equivalence of null and dominant missense disease.
PMID:29180951 SUPPORT DIRECT PRIMARY RESULT In Vitro
"These results suggest that P2X2 dominant deafness mutations do not have negative effects on WT P2X2 isoforms, and that adding additional WT P2X2 could rescue the lost channel function caused by the deafness mutations."
Coexpression evidence challenges a universal dominant-negative interpretation; this is cellular functional rescue, not demonstrated hearing therapy.
PMID:31636190 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains."
Gain of basal conductance coexists with loss of ATP regulation in this assay.
+ 1 more reference
P2RX2 is classified Moderate rather than Definitive for dominant nonsyndromic hearing loss. What would move it, and does the strength of the mechanistic evidence make the human genetic evidence look better than it is?
KNOWLEDGE GAP dfna41_gene_disease_validity
Attached to
genetic#P2RX2 disease#Autosomal Dominant Nonsyndromic Hearing Loss 41
ClinGen's September 2022 evaluation scored three variants in four probands and retained Moderate validity. New segregation and population data require allele-level assessment. Functional results support biological relevance but cannot substitute for independent human genetic evidence, especially for p.Asp273Tyr with conflicting population data.
Show evidence (4 references)
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other
"In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged."
The panel's summary judgement, in its own words.
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other
"Three missense variants that have been reported in four probands in four publications are included in this curation"
The size of the human genetic evidence base, which is the specific thing that is thin - not the mechanism.
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other
"Although a new case with hearing loss (29986705) and a new knock-in mouse model with progressive hearing loss (33791800) were scored, the classification did not change (SOP Version 9)."
The 2022 reevaluation, which is informative about what does not move a classification: an additional case and the allele-matched knock-in this entry relies on were both scored and left it at Moderate.
+ 1 more reference
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Pathophysiology

3
Variant-Specific P2X2 Channel Dysfunction
Mechanism confidence: Established
P2RX2 p.Val60Leu and p.Gly353Arg alter P2X2 channel function. Early p.Val60Leu experiments found absent ATP-evoked current and reduced ATP-stimulated dye uptake. Subsequent studies found constitutive ATP-insensitive conductance for p.Val60Leu and ATP-responsive p.Gly353Arg channels with altered sensitivity, rectification and ion selectivity. In 2025, p.Val60Leu showed fluorescent-ATP binding, small ATP-evoked currents and reduced cell viability; constitutive activity was not reproduced under those conditions. These findings support abnormal gating and coupling rather than universally absent channels or ATP binding. Wild-type/mutant coexpression reduced permeability in the original study, but a later coexpression study retained robust ATP responses and argued against poisoning of wild-type P2X2. The dominant clinical inheritance is established for these alleles; its precise molecular basis remains disputed. P2X2/P2X3 heteromer experiments are distinct from mutant/wild-type P2X2 coexpression. Functional abnormalities of the uncertain p.Asp201Tyr/p.Asp273Tyr variant do not independently prove human disease causality.
None
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee. allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS
Heterozygous germline P2RX2 missense variants with allele-specific channel abnormalities; dominant-negative interference is proposed but contested. The Iranian variant is missense on the matched reference transcript, despite its original stop-loss annotation on an alternate transcript.
extracellularly ATP-gated monoatomic cation channel activity GO:0004931 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal extracellularly ATP-gated monoatomic cation channel activity (GO:0004931). GO:0004931 is a molecular function from the Gene Ontology.
Experimental models
Patient-derived P2RX2 p.Val60Leu hiPSC lines and their CRISPR homozygous isogenic control IPSC DERIVED MODEL Establishes the p.Val60Leu allele at two dosages in a human genetic background: the patients' own heterozygous state, and an engineered homozygote as a control for gene function.
Human p.Val60Leu hiPSC Allele-Selective Editing IPSC DERIVED MODEL Allele-selective disruption targets the variant underlying the channel-dysfunction node.
Downstream
Loss of Purinergic Adaptation to Elevated Sound Levels Inferred tissue consequence of allele-specific channel dysfunction; not directly established by heterologous-cell assays. None
Inner Hair Cell and Ribbon Synapse Disorganisation Inferred tissue consequence of allele-specific channel dysfunction; not directly established by heterologous-cell assays. None
Show evidence (6 references)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT In Vitro
"P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling."
The direct electrophysiological and permeability measurement of the founding allele.
PMID:29180951 SUPPORT DIRECT PRIMARY RESULT In Vitro
"These results suggest that P2X2 dominant deafness mutations do not have negative effects on WT P2X2 isoforms, and that adding additional WT P2X2 could rescue the lost channel function caused by the deafness mutations."
Coexpression evidence challenges a universal dominant-negative interpretation; this is cellular functional rescue, not demonstrated hearing therapy.
PMID:31636190 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains."
Gain of basal conductance coexists with loss of ATP regulation in this assay.
+ 3 more references
Loss of Purinergic Adaptation to Elevated Sound Levels
Mechanism confidence: Provisional
P2rx2-null mice lack the purinergic component of adaptation to sustained sound. Under the studied 85 dB SPL noise protocols, wild-type mice developed temporary ABR threshold shifts and reduced cochlear gain, whereas null mice showed greatly reduced adaptation. At higher levels, other processes contributed to temporary threshold shifts and null mice were more susceptible to permanent loss. These protocols do not establish a human safe-exposure threshold or imply that all temporary hearing changes are noninjurious. ATP-induced cochlear partition conductance and endocochlear-potential changes were absent in null mice. The acute cation shunt alone does not explain the prolonged threshold recovery; downstream processes remain incompletely defined. Heterozygous null littermates retained adaptation, supporting haplosufficiency in this assay. Extrapolation to heterozygous human missense disease therefore requires allele-specific testing.
None
cochlear outer hair cell CL:0000601 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear outer hair cell (CL:0000601). CL:0000601 is a cell type from the Cell Ontology. supporting cell CL:0000630 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves supporting cell (CL:0000630). CL:0000630 is a cell type from the Cell Ontology.
purinergic nucleotide receptor signaling pathway GO:0035590 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased purinergic nucleotide receptor signaling pathway (GO:0035590). GO:0035590 is a biological process from the Gene Ontology.
Animal models
P2rx2 null mouse Mouse recapitulates Defines loss of purinergic adaptation using ABR, otoacoustic emissions, cellular currents and cochlear partition conductance.
Downstream
Inner Hair Cell and Ribbon Synapse Disorganisation Supported by mouse noise-susceptibility experiments, with the contribution in human variant carriers still inferred. None
Noise-Exacerbated High-Frequency Hearing Impairment Supported by mouse noise-susceptibility experiments, with the contribution in human variant carriers still inferred. None
Show evidence (6 references)
PMID:23592720 SUPPORT DIRECT PRIMARY RESULT Model Organism
"We show that ATP-gated ion channels assembled from P2X2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise."
The central claim of this node, established in the null mouse.
PMID:23592720 SUPPORT DIRECT PRIMARY RESULT Model Organism
"In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
Protocol-specific loss of adaptation in null mice; not a universal safe sound level.
PMID:23592720 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment."
Proposed noise-triggered ATP signaling route, explicitly inferred.
+ 3 more references
Inner Hair Cell and Ribbon Synapse Disorganisation
Mechanism confidence: Provisional
Heterozygous p.Val61Leu mice show shortened inner hair cells and abnormal perinuclear positioning of ribbon synapses. Early abnormalities occurred without overt hair-cell loss; ribbon counts were increased at four months rather than simply depleted. Later degeneration was documented in the genome-editing study. These model findings are not established human temporal-bone pathology. The knockout noise experiments independently measured loss of ribbon-synapse puncta and afferent terminals after intense exposure. Noise-induced synapse attrition and spontaneous knock-in ribbon mislocalization are distinct findings. Their molecular connection to altered P2X2 gating remains uncertain.
cochlear inner hair cell CL:0000589 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlear inner hair cell (CL:0000589). CL:0000589 is a cell type from the Cell Ontology.
Animal models
P2rx2 V61L knock-in mouse Mouse recapitulates Allele-matched cochlear structural phenotype in mice, with early ribbon mislocalization and later degeneration.
Downstream
Progressive Sensorineural Hearing Impairment Structural and auditory abnormalities co-occur in mice; their specific causal contribution has not been isolated.
Show evidence (2 references)
PMID:33791800 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
The structural finding in the allele-matched knock-in, stated with the authors' hedge about what it suggests.
PMID:23592720 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption."
Null-mouse noise injury is complementary evidence, distinct from knock-in ribbon mislocalization.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Nonsyndromic Hearing Loss 41 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Ear 3
Progressive Sensorineural Hearing Impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408), qualified as laterality bilateral. HP:0000408 is a phenotype from the Human Phenotype Ontology.
Laterality: BILATERAL
The follow-up abstract reports onset at 25–35 years, whereas the original full article reports 12–20 years and elevated thresholds in some carriers as early as 6–10. Full follow-up text was not accessible in this review, so the discrepancy is retained without selecting one range as universal. The Iranian candidate-variant family included congenital deafness; its uncertain variant interpretation prevents a universal onset claim.
Show evidence (8 references)
PMID:31593348 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Progressive hearing impairment was confirmed by history and by audiological follow-up testing in all the patients."
Progression established prospectively rather than by recall, in a ten-year follow-up of the founding family.
PMID:31593348 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences."
Bilaterality and the all-frequency configuration in the same cohort.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Sensorineural hearing loss due to malfunction of the inner ear structures (i.e., cochlea or auditory nerve, with potential for vestibular dysfunction)"
General clinical definition; disease-specific progression is supported by the family studies.
+ 5 more references
Noise-Exacerbated High-Frequency Hearing Impairment High-frequency sensorineural hearing impairment HP:0001757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-frequency sensorineural hearing impairment (HP:0001757). HP:0001757 is a phenotype from the Human Phenotype Ontology.
No individual-level frequency estimate is inferred from the exposed/unexposed family comparison.
Show evidence (2 references)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
The human observation of the gene-environment interaction.
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Model Organism
"P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
The matching result in mice, where exposure could be controlled rather than recalled.
Tinnitus HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360). HP:0000360 is a phenotype from the Human Phenotype Ontology.
frequency is deliberately absent. The source says "in one family" out of the four probands curated, which is a count of families rather than of affected individuals, so there is no patient denominator to grade a FrequencyEnum band against.
Show evidence (2 references)
CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other
"The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family."
The expert-panel summary of the reported DFNA41 families, which is where the tinnitus is recorded. Graded OTHER because a ClinGen curation is an expert reading of other people's cases rather than a study reporting its own.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3568371/?report=reader SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Audiologic evaluation of family members revealed bilateral and symmetrical sensorineural hearing loss, with age at onset ranging from 12 y to 20 y, generally accompanied by high-frequency tinnitus."
Full-text clinical characterization of the index family; other reports give different onset ranges.
Nervous System 1
Hyperalgesia Dysesthesia HP:0012534 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperalgesia, annotated with Dysesthesia (HP:0012534). HP:0012534 is a phenotype from the Human Phenotype Ontology.
Reported in one human family without a sufficiently detailed denominator in the accessible abstract to estimate frequency. HP:0012534 includes Hyperalgesia as a synonym.
Show evidence (1 reference)
PMID:39258340 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We quantitatively evaluated the pain perception ability of some members using the Pain Vision PS-2100 system, and further found an interesting clinical manifestation, that is, hyperalgesia, in heterozygotes for P2RX2 p.V60L."
The measurement and the genotype it was made in. Quantitative rather than symptom-report, which matters for a finding this easy to dismiss.
🧬

Genetic Associations

1
P2RX2
Gene: P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (9 references)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea."
The gene-disease relationship and the cell types in which the receptor acts.
PMID:24211385 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL."
The first independent replication, and its hedged wording is preserved because at that point the gene rested on two families.
PMID:25788561 NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing."
Segregation in a family also carrying the hearing-loss-associated mitochondrial variant does not establish independent P2RX2 causality.
+ 6 more references
💊

Medical Actions

5
Hearing Conservation and Noise Avoidance
Platform: Behavioral / lifestyle
Avoid repeated overexposure to loud sound and use hearing protection appropriate to exposure. This is general hearing-loss guidance with additional rationale from the observed DFNA41 noise association. Disease-specific benefit size and a safe carrier exposure limit have not been established.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided."
General hearing-conservation recommendation.
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
The human evidence that noise exposure modifies the phenotype in carriers, which is what justifies curating it as an environmental entry at all.
Genetic Counselling with Audiologic Surveillance
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Provide counseling on variant interpretation, variable onset/severity and the 50% probability of transmission from a heterozygous parent with a causal dominant allele. Offer appropriate testing of relatives and serial audiologic assessment, including before symptoms when a familial variant is known.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child."
Mendelian transmission probability after establishing a causal dominant allele; not a universal penetrance estimate.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Regular follow up is recommended for all individuals with genetic hearing loss"
General surveillance recommendation; tailor frequency to age and hearing trajectory.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted."
Transmission probability does not establish age-specific penetrance or severity.
Cochlear Implantation
Action: cochlear implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as Medical Device Cochlear Implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Implantation for an ear that has reached profound loss. The reported DFNA41 experience is a single proband from a five-generation Chinese kindred carrying p.Val60Leu, with a satisfactory outcome. That family is also the one with earlier onset and worse hearing than the original DFNA41 families, so it is the part of the phenotypic range where implantation becomes relevant.
Show evidence (2 references)
PMID:39258340 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The cochlear implant (CI) was also provided for the proband of profound deafness, resulting in satisfactory clinical outcomes."
The implantation and its outcome in a molecularly confirmed DFNA41 proband.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language."
General hearing-loss care; no DFNA41-specific efficacy estimate is inferred.
Hearing Aids and Communication Rehabilitation
Action: hearing rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing rehabilitation, annotated with Rehabilitation (NCIT:C15315), qualified as Medical Device Hearing Aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Individualize amplification, communication support and hearing habilitation according to measured hearing and communication needs. Use standard care even when genotype-specific outcome series are unavailable.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language."
General hearing-loss care; no DFNA41-specific efficacy estimate is inferred.
Experimental Allele-Selective Genome Editing
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene therapy
Preclinical AAV2–SaCas9 disruption of the mutant allele preserved selected auditory frequencies, cochlear cells and vestibular performance in heterozygous p.Val61Leu mice. Earlier treatment broadened preservation. A human-specific guide edited patient-derived hiPSCs. These findings do not establish human efficacy or safety; no P2RX2/DFNA41 study was returned by the ClinicalTrials.gov queries on 2026-09-23.
Show evidence (2 references)
PMID:41090360 SUPPORT DIRECT PRIMARY RESULT Model Organism
"These findings demonstrate that AAV2–SaCas9–sgRNA-1 editing therapy provides robust and long-term preservation of hearing at specific frequencies in P2rx2V61L/+ mice."
Measured preclinical hearing preservation, not complete normalization.
PMID:41090360 SUPPORT DIRECT PRIMARY RESULT In Vitro
"NGS analysis revealed robust indel generation in cells edited with SaCas9-KKH/sgRNA-1, with an indel frequency of 37.9% ± 2.3%"
Human patient-derived cell editing; no auditory functional readout.
🌍

Environmental Factors

1
Occupational and recreational noise exposure
exposure to sound radiation ECTO:8000044 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to sound radiation (ECTO:8000044). ECTO:8000044 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Noise is a modifier of genetically determined hearing loss. Human carrier observations and controlled mouse experiments support increased susceptibility, but no genotype-specific human exposure threshold is established.
Show evidence (1 reference)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
The human evidence that noise exposure modifies the phenotype in carriers, which is what justifies curating it as an environmental entry at all.
Mechanism Target:
EXACERBATES Noise-Exacerbated High-Frequency Hearing Impairment — Noise exposure is associated with worse high-frequency hearing in carriers and causes greater injury in the studied mouse models; dose, timing and molecular intermediates differ between systems.
Show evidence (2 references)
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood."
Retrospective exposure-outcome association in a family, not a controlled human intervention.
PMID:23345450 SUPPORT DIRECT PRIMARY RESULT Model Organism
"P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults."
The controlled-exposure counterpart in mice, where the noise history is known rather than recalled.
🔬

Diagnosis

1
Audiologic and Molecular Diagnosis
Assess onset, progression, bilateral thresholds, speech understanding, family history and noise exposure. Use a multigene hearing-loss panel or genomic testing with variant interpretation; targeted family testing is appropriate once a causal variant is known. Normal childhood hearing does not exclude later loss, but childhood presentations also occur. A P2RX2 VUS, including an allele with conflicting population evidence, does not confirm DFNA41. Consider coexisting mitochondrial or other causes when clinically indicated.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of uncertain significance in genes that are irrelevant to the underlying phenotype"
General testing guidance, applied to the heterogeneous hearing-loss differential.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis."
Prevents gene membership or functional assays alone from being treated as a molecular diagnosis.
PMID:31593348 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences."
Bilaterality and the all-frequency configuration in the same cohort.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature
Published families and selected hearing-loss cohorts establish rarity of reported cases but do not provide a population prevalence estimate. The Japanese P2RX2 candidate is confounded by mitochondrial disease and is not counted as an unequivocal causal diagnosis.
Show evidence (1 reference)
PMID:25788561 NO_EVIDENCE DIRECT PRIMARY RESULT Human Clinical
"One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study."
An ascertained hearing-loss cohort is not a population prevalence denominator, and the P2RX2 finding itself remains uncertain.
🧫

Experimental Models

2
Patient-derived P2RX2 p.Val60Leu hiPSC lines and their CRISPR homozygous isogenic control IPSC_DERIVED_MODEL
Patient-derived heterozygous p.Val60Leu hiPSCs were generated from urine epithelial cells, and CRISPR/ssODN editing introduced the same variant into the remaining allele to create a homozygous dosage model. The 2019 paper established pluripotency and genotype without otic differentiation or channel-functional rescue.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Non-integrative hiPSCs reprogrammed from urine-derived epithelial cells of three members of a large Chinese kindred heterozygous for P2RX2 c.178G>T (p.Val60Leu).
Publication
PMID:30819013
Pathograph links
Variant-Specific P2X2 Channel Dysfunction perturbs fidelity: unknown Establishes the p.Val60Leu allele at two dosages in a human genetic background: the patients' own heterozygous state, and an engineered homozygote as a control for gene function.
Limitations: Undifferentiated hiPSCs and an engineered homozygous allele-dosage control do not establish cochlear physiology or a human homozygous disease phenotype.
Show evidence (1 reference)
PMID:30819013 SUPPORT DIRECT PRIMARY RESULT In Vitro
"we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function."
The editing step that makes this a dosage series for the node rather than a single patient line.
The paper labels mutant lines P2RX2+/- and P2RX2-/-, but these carry one or two missense alleles, not deletion alleles. A later study used patient-derived hiPSCs for mutation-selective editing.
Show evidence (1 reference)
PMID:30819013 SUPPORT DIRECT PRIMARY RESULT In Vitro
"We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL."
The derivation of the patient lines and the allele they carry.
Human p.Val60Leu hiPSC Allele-Selective Editing IPSC_DERIVED_MODEL
SaCas9-KKH/sgRNA-1 generated predominantly frameshifting indels in patient-derived hiPSCs. Healthy control hiPSCs showed no detected indels; targeted testing of predicted off-target sites found none. These assays establish editing feasibility within their detection limits, not cochlear efficacy or comprehensive safety.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:41090360
Pathograph links
Variant-Specific P2X2 Channel Dysfunction perturbs fidelity: unknown observes: molecular Allele-selective disruption targets the variant underlying the channel-dysfunction node.
Limitations: Editing efficiency was measured in undifferentiated cells; channel function and cochlear rescue were not measured in this human model.
Show evidence (1 reference)
PMID:41090360 SUPPORT DIRECT PRIMARY RESULT In Vitro
"NGS analysis revealed robust indel generation in cells edited with SaCas9-KKH/sgRNA-1, with an indel frequency of 37.9% ± 2.3%"
Human patient-derived cell editing; no auditory functional readout.
Show evidence (1 reference)
PMID:41090360 SUPPORT DIRECT PRIMARY RESULT In Vitro
"NGS analysis revealed robust indel generation in cells edited with SaCas9-KKH/sgRNA-1, with an indel frequency of 37.9% ± 2.3%"
Human patient-derived cell editing; no auditory functional readout.
🐁

Animal Models

4
P2rx2 V61L knock-in mouse
The heterozygous mouse counterpart of human p.Val60Leu develops progressive hearing loss from postnatal day 21, with shortened inner hair cells, displaced synaptic ribbons, balance deficits and increased hot-plate sensitivity. Its time course and genetic background differ from human disease.
Species
Mouse
Genotype
P2rx2 p.Val61Leu/+ knock-in, corresponding to human p.Val60Leu
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:33791800
Pathograph links
Inner Hair Cell and Ribbon Synapse Disorganisation recapitulates fidelity: moderate Allele-matched cochlear structural phenotype in mice, with early ribbon mislocalization and later degeneration.
Limitations: Human cochlear histopathology has not been demonstrated in the reviewed sources. Human onset varies, and mouse progression over months is not a direct age equivalent. Vestibular dysfunction remains a model observation: the 2019 patient-derived cell paper reports clinical vestibular testing in its methods, while the 2025 editing paper states human dysfunction has not been reported.
Readouts
Inner hair cell and ribbon synapse morphology
Direction: ALTERED
Interpretation: Progressive morphological abnormality rather than an all-or-none defect, appearing over the same period as the hearing decline.
Show evidence (1 reference)
PMID:33791800 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
The structural measurement behind this readout.
Show evidence (1 reference)
PMID:33791800 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses."
The structural finding in the allele-matched knock-in, stated with the authors' hedge about what it suggests.
P2rx2 null mouse
The model in which the purinergic adaptation mechanism was established. Nulls lack ATP-gated conductance across the cochlear partition including ATP-gated inward current in hair cells, fail to develop the temporary threshold shift that wild-type mice develop under sustained 85 dB noise, and are more vulnerable than wild-type mice to permanent loss at 95 dB and above.
Species
Mouse
Genotype
P2rx2 null, homozygous
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:23592720
Pathograph links
Loss of Purinergic Adaptation to Elevated Sound Levels recapitulates fidelity: moderate Defines loss of purinergic adaptation using ABR, otoacoustic emissions, cellular currents and cochlear partition conductance.
Limitations: Homozygous deletion differs from heterozygous human missense disease. Heterozygous null mice retained temporary-threshold adaptation. Background strain and noise protocol also limit extrapolation; constitutive and altered-gating effects of missense variants are not modeled by a null.
Readouts
Noise-induced temporary threshold shift
Direction: ABOLISHED
Interpretation: The adaptive response to moderate sustained noise does not occur in the absence of P2X2. This is the defining measurement of the node.
Show evidence (1 reference)
PMID:23592720 SUPPORT DIRECT PRIMARY RESULT Model Organism
"In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed."
The threshold-shift measurement in the null.
ATP-gated conductance across the cochlear partition
Direction: ABOLISHED
Interpretation: Direct electrophysiological evidence that ATP-evoked conductance is absent; the ABR endpoint is also an electrophysiological measurement.
Show evidence (1 reference)
PMID:23592720 SUPPORT DIRECT PRIMARY RESULT Model Organism
"P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells."
The direct conductance measurement in the null.
Show evidence (1 reference)
PMID:23592720 SUPPORT DIRECT PRIMARY RESULT Model Organism
"These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing."
The conclusion this node curates, drawn from this model.
P2rx2 V61L knock-in mouse treated with AAV-delivered SaCas9
Local AAV2–SaCas9 editing of heterozygous p.Val61Leu mice preserved hearing at selected frequencies and attenuated noise-induced loss. Four-week treatment preserved low/mid-frequency responses for nine months; juvenile treatment broadened benefit. Cell survival and vestibular readouts also improved. Assays found no detectable cochlear target-site AAV integration at the tested dose, but cultured cells showed dose-dependent integration.
Species
Mouse
Genotype
P2rx2 V61L/+ knock-in treated with AAV2 SaCas9-sgRNA targeting the mutant allele
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:41090360
Show evidence (1 reference)
PMID:41090360 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Intervention in mice at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention."
Earlier mouse intervention broadened the range of preserved auditory frequencies; it does not imply human diagnosis must wait until adulthood.
p2rx2 knockout zebrafish
A homozygous p2rx2 loss-of-function zebrafish line with a 66-base insertion introducing a premature TAA. Larval otolith-region hair-cell staining density was reduced while lateral-line counts were unchanged; adult auditory-evoked thresholds were elevated.
Species
Zebrafish
Genotype
p2rx2 knockout (66 bp insertion introducing a premature TAA), homozygous
Genes
P2RX2 hgnc:15459 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns P2RX2 (hgnc:15459). hgnc:15459 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:41015553
{ }

Source YAML

click to show 
name: Autosomal Dominant Nonsyndromic Hearing Loss 41
category: Mendelian
creation_date: '2026-08-28T00:00:00Z'
synonyms:
- DFNA41
- deafness, autosomal dominant 41
- P2RX2 autosomal dominant nonsyndromic deafness
- autosomal dominant nonsyndromic deafness caused by mutation in P2RX2
- autosomal dominant nonsyndromic deafness type 41
- deafness, autosomal dominant type 41
- autosomal dominant deafness 41
- autosomal dominant nonsyndromic deafness 41
description: 'DFNA41 is autosomal dominant progressive sensorineural hearing loss associated with heterozygous P2RX2 variants. The best-supported alleles include p.Val60Leu and p.Gly353Arg. Age at recognition varies across families and publications; childhood/adolescent presentations preclude treating it as exclusively adult-onset. Occupational noise exposure was associated with poorer high-frequency hearing among p.Val60Leu carriers. Hyperalgesia was reported in one additional family, and a profoundly deaf proband benefited from cochlear implantation.

  P2X2 is an ATP-gated cation channel. The functional defect is allele- and assay-dependent: p.Val60Leu has markedly impaired ATP-evoked responses, with constitutive activity in a 2019 study but small ATP-triggered currents and reduced cell viability in a 2025 study. p.Gly353Arg retains channel activity with altered ATP sensitivity, rectification and ion selectivity. A universal dominant-negative mechanism is not established. P2rx2-null mice demonstrate a protective purinergic component of adaptation to sustained sound; this does not mean all temporary threshold shifts are harmless. The connection between specific human channel defects, adaptation and progressive cochlear injury remains incompletely resolved.

  Allele-selective genome editing preserved hearing at selected frequencies and reduced noise susceptibility in heterozygous p.Val61Leu mice, the mouse counterpart of human p.Val60Leu. This is preclinical evidence, supplemented by editing in human patient-derived cells. ClinGen''s September 2022 gene-disease classification remains Moderate in the reviewed assertion; variant-specific interpretation is essential.'
disease_term:
  preferred_term: autosomal dominant nonsyndromic hearing loss 41
  term:
    id: MONDO:0011994
    label: autosomal dominant nonsyndromic hearing loss 41
parents:
- Autosomal Dominant Nonsyndromic Hearing Loss
inheritance:
- name: Autosomal dominant
  description: Heterozygous disease-causing P2RX2 variants segregate with dominant hearing loss. Full penetrance was reported in the original p.Val60Leu index pedigree; it is not established for every P2RX2 variant. A heterozygous affected parent has a 50% probability of transmitting the variant per pregnancy, independently of the severity or timing of expression.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in a second family with the same phenotype.
    explanation: Dominant segregation and full penetrance in the index family; the second family supplies additional segregation evidence.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:24211385
    reference_title: A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus.
    explanation: Independent linkage evidence for dominant inheritance at the same locus.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child.
    explanation: Mendelian transmission probability after establishing a causal dominant allele; not a universal penetrance estimate.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: Variant-Specific P2X2 Channel Dysfunction
  description: 'P2RX2 p.Val60Leu and p.Gly353Arg alter P2X2 channel function. Early p.Val60Leu experiments found absent ATP-evoked current and reduced ATP-stimulated dye uptake. Subsequent studies found constitutive ATP-insensitive conductance for p.Val60Leu and ATP-responsive p.Gly353Arg channels with altered sensitivity, rectification and ion selectivity. In 2025, p.Val60Leu showed fluorescent-ATP binding, small ATP-evoked currents and reduced cell viability; constitutive activity was not reproduced under those conditions. These findings support abnormal gating and coupling rather than universally absent channels or ATP binding.

    Wild-type/mutant coexpression reduced permeability in the original study, but a later coexpression study retained robust ATP responses and argued against poisoning of wild-type P2X2. The dominant clinical inheritance is established for these alleles; its precise molecular basis remains disputed. P2X2/P2X3 heteromer experiments are distinct from mutant/wild-type P2X2 coexpression. Functional abnormalities of the uncertain p.Asp201Tyr/p.Asp273Tyr variant do not independently prove human disease causality.'
  biological_scale: MOLECULAR
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  genetic_context:
    gene:
      preferred_term: P2RX2
      term:
        id: hgnc:15459
        label: P2RX2
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: Heterozygous germline P2RX2 missense variants with allele-specific channel abnormalities; dominant-negative interference is proposed but contested. The Iranian variant is missense on the matched reference transcript, despite its original stop-loss annotation on an alternate transcript.
  molecular_functions:
  - preferred_term: extracellularly ATP-gated monoatomic cation channel activity
    term:
      id: GO:0004931
      label: extracellularly ATP-gated monoatomic cation channel activity
    modifier: ABNORMAL
  downstream:
  - target: Loss of Purinergic Adaptation to Elevated Sound Levels
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Inferred tissue consequence of allele-specific channel dysfunction; not directly established by heterologous-cell assays.
    hypothesis_groups:
    - dfna41_channel_to_cochlear_injury
  - target: Inner Hair Cell and Ribbon Synapse Disorganisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Inferred tissue consequence of allele-specific channel dysfunction; not directly established by heterologous-cell assays.
    hypothesis_groups:
    - dfna41_channel_to_cochlear_injury
  evidence:
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling.'
    explanation: The direct electrophysiological and permeability measurement of the founding allele.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:29180951
    reference_title: 'P2X2 Dominant Deafness Mutations Have No Negative Effect on Wild-Type Isoform: Implications for Functional Rescue and in Deafness Mechanism.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These results suggest that P2X2 dominant deafness mutations do not have negative effects on WT P2X2 isoforms, and that adding additional WT P2X2 could rescue the lost channel function caused by the deafness mutations.
    explanation: Coexpression evidence challenges a universal dominant-negative interpretation; this is cellular functional rescue, not demonstrated hearing therapy.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:31636190
    reference_title: Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains.
    explanation: Gain of basal conductance coexists with loss of ATP regulation in this assay.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:31636190
    reference_title: Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, the G353R mutant can be activated by ATP but exhibits alterations in sensitivity to ATP, inward rectification, and ion selectivity.
    explanation: Direct functional evidence for the second allele; a nonfunctional-channel claim would be inaccurate.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40214464
    reference_title: Differential Effects of Hearing Loss Mutations in Homomeric P2X2 and Heteromeric P2X2/3 Receptors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We observed robust binding to fATP, but no channels with an intrinsic open probability. Upon ATP application, we measured currents, although they were minimal compared with the wt P2X2 receptor.
    explanation: Later p.Val60Leu results differ from constitutive activation reported in 2019; assay differences remain unresolved.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40214464
    reference_title: Differential Effects of Hearing Loss Mutations in Homomeric P2X2 and Heteromeric P2X2/3 Receptors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Both P2X2 V60L and P2X2/3 V60L cell lines with an induction of expression showed a decrease in the luminescence signal 48 h after induction.
    explanation: Reduced viability in heterologous cells supports possible cellular toxicity, not direct demonstration of human cochlear cell death.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  mechanism_confidence: ESTABLISHED
- name: Loss of Purinergic Adaptation to Elevated Sound Levels
  description: 'P2rx2-null mice lack the purinergic component of adaptation to sustained sound. Under the studied 85 dB SPL noise protocols, wild-type mice developed temporary ABR threshold shifts and reduced cochlear gain, whereas null mice showed greatly reduced adaptation. At higher levels, other processes contributed to temporary threshold shifts and null mice were more susceptible to permanent loss. These protocols do not establish a human safe-exposure threshold or imply that all temporary hearing changes are noninjurious.

    ATP-induced cochlear partition conductance and endocochlear-potential changes were absent in null mice. The acute cation shunt alone does not explain the prolonged threshold recovery; downstream processes remain incompletely defined. Heterozygous null littermates retained adaptation, supporting haplosufficiency in this assay. Extrapolation to heterozygous human missense disease therefore requires allele-specific testing.'
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cochlear outer hair cell
    term:
      id: CL:0000601
      label: cochlear outer hair cell
  - preferred_term: supporting cell
    term:
      id: CL:0000630
      label: supporting cell
  biological_processes:
  - preferred_term: purinergic nucleotide receptor signaling pathway
    term:
      id: GO:0035590
      label: purinergic nucleotide receptor signaling pathway
    modifier: DECREASED
  downstream:
  - target: Inner Hair Cell and Ribbon Synapse Disorganisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Supported by mouse noise-susceptibility experiments, with the contribution in human variant carriers still inferred.
    hypothesis_groups:
    - dfna41_channel_to_cochlear_injury
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Supported by mouse noise-susceptibility experiments, with the contribution in human variant carriers still inferred.
    hypothesis_groups:
    - dfna41_channel_to_cochlear_injury
  evidence:
  - reference: PMID:23592720
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We show that ATP-gated ion channels assembled from P2X2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise.
    explanation: The central claim of this node, established in the null mouse.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23592720
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed.
    explanation: Protocol-specific loss of adaptation in null mice; not a universal safe sound level.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23592720
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment.
    explanation: Proposed noise-triggered ATP signaling route, explicitly inferred.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:23592720
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption.
    explanation: At higher tested exposures, temporary shifts had additional components and permanent injury was greater in null mice.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23592720
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing.
    explanation: Only a component of temporary threshold shift is assigned to adaptive P2X2 signaling.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645545/
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data indicate haplosufficiency in the development of P2X ... receptor-dependent TTS.
    explanation: Heterozygous null mice retained adaptation, preventing direct equivalence of null and dominant missense disease.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  mechanism_confidence: PROVISIONAL
- name: Inner Hair Cell and Ribbon Synapse Disorganisation
  description: 'Heterozygous p.Val61Leu mice show shortened inner hair cells and abnormal perinuclear positioning of ribbon synapses. Early abnormalities occurred without overt hair-cell loss; ribbon counts were increased at four months rather than simply depleted. Later degeneration was documented in the genome-editing study. These model findings are not established human temporal-bone pathology.

    The knockout noise experiments independently measured loss of ribbon-synapse puncta and afferent terminals after intense exposure. Noise-induced synapse attrition and spontaneous knock-in ribbon mislocalization are distinct findings. Their molecular connection to altered P2X2 gating remains uncertain.'
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cochlear inner hair cell
    term:
      id: CL:0000589
      label: cochlear inner hair cell
  downstream:
  - target: Progressive Sensorineural Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Structural and auditory abnormalities co-occur in mice; their specific causal contribution has not been isolated.
  evidence:
  - reference: PMID:33791800
    reference_title: Generation and characterization of a P2rx2 V60L mouse model for DFNA41.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses.
    explanation: The structural finding in the allele-matched knock-in, stated with the authors' hedge about what it suggests.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23592720
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption.
    explanation: Null-mouse noise injury is complementary evidence, distinct from knock-in ribbon mislocalization.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  mechanism_confidence: PROVISIONAL
phenotypes:
- name: Progressive Sensorineural Hearing Impairment
  category: Auditory
  description: Bilateral sensorineural hearing loss involving all frequencies, worsening over decades, confirmed both by history and by audiological follow-up in the original kindred at ten-year review.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
    laterality: BILATERAL
    onset:
      notes: Usually postlingual, with reported childhood, adolescent and adult onset. The original family had onset at 12–20 years and some raised thresholds at 6–10; its ten-year follow-up abstract reports 25–35 years. These reports are not reconciled by the available follow-up abstract.
  evidence:
  - reference: PMID:31593348
    reference_title: 'Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Progressive hearing impairment was confirmed by history and by audiological follow-up testing in all the patients.
    explanation: Progression established prospectively rather than by recall, in a ten-year follow-up of the founding family.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:31593348
    reference_title: 'Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences.
    explanation: Bilaterality and the all-frequency configuration in the same cohort.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sensorineural hearing loss due to malfunction of the inner ear structures (i.e., cochlea or auditory nerve, with potential for vestibular dysfunction)
    explanation: General clinical definition; disease-specific progression is supported by the family studies.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:31593348
    reference_title: 'Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The onset of hearing loss was between age 25 and 35 years.
    explanation: Adult onset reported in the follow-up abstract; retained alongside conflicting earlier observations, not generalized to all carriers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39258340
    reference_title: Novel Clinical Manifestation and Favorable Treatment Outcome of Cochlear Implant in a Chinese Family With Likely Pathogenic Variant of the P2RX2 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite carrying the same variant, the affected members in this family appear to present with earlier-onset hearing loss and poorer hearing compared to the original DFNA41 families.
    explanation: Independent family with earlier presentation supports variability of onset.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3568371/?report=reader
    reference_title: Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Some family members exhibited elevated thresholds at one or more frequencies as early as age 6–10 y, suggesting that this loss may begin at an even earlier age.
    explanation: Primary full-text observation establishes childhood threshold abnormalities in some carriers.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family.
    explanation: Expert-panel synthesis of the principal families. Its broad summary does not override the congenital presentation documented for the Iranian candidate variant.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:29986705
    reference_title: Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: OTO.003 | Bilateral non-syndromic sensorineural deafness | AD | Childhood | P2RX2 | c.178G > T p.(Val60Leu)
    explanation: Spanish clinical-series observation supports childhood onset; it does not establish whether onset preceded or followed language acquisition.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  notes: The follow-up abstract reports onset at 25–35 years, whereas the original full article reports 12–20 years and elevated thresholds in some carriers as early as 6–10. Full follow-up text was not accessible in this review, so the discrepancy is retained without selecting one range as universal. The Iranian candidate-variant family included congenital deafness; its uncertain variant interpretation prevents a universal onset claim.
- name: Noise-Exacerbated High-Frequency Hearing Impairment
  category: Auditory
  description: Occupational noise history was associated with poorer high-frequency thresholds among p.Val60Leu carriers in the original family. Controlled noise exposure in null and knock-in mice provides complementary experimental support; the human comparison is observational.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  evidence:
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood.
    explanation: The human observation of the gene-environment interaction.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults.
    explanation: The matching result in mice, where exposure could be controlled rather than recalled.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: No individual-level frequency estimate is inferred from the exposed/unexposed family comparison.
- name: Tinnitus
  category: Auditory
  description: Ringing or other phantom sound accompanying the hearing loss. ClinGen's Hearing Loss expert panel, reviewing the four probands on which the P2RX2 gene-disease relationship rests, records tinnitus in one of the reported families.
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The hearing loss in these families had a postlingual onset, was progressive, and co-occurred with tinnitus in one family.
    explanation: The expert-panel summary of the reported DFNA41 families, which is where the tinnitus is recorded. Graded OTHER because a ClinGen curation is an expert reading of other people's cases rather than a study reporting its own.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3568371/?report=reader
    reference_title: Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Audiologic evaluation of family members revealed bilateral and symmetrical sensorineural hearing loss, with age at onset ranging from 12 y to 20 y, generally accompanied by high-frequency tinnitus.
    explanation: Full-text clinical characterization of the index family; other reports give different onset ranges.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  notes: frequency is deliberately absent. The source says "in one family" out of the four probands curated, which is a count of families rather than of affected individuals, so there is no patient denominator to grade a FrequencyEnum band against.
- name: Hyperalgesia
  category: Neurologic
  description: Quantitative Pain Vision testing identified increased pain sensitivity in some p.Val60Leu heterozygotes from a five-generation Chinese family. Its prevalence and mechanism across DFNA41 remain uncertain. Pain hypersensitivity was also measured in the knock-in mouse.
  phenotype_term:
    preferred_term: Hyperalgesia
    term:
      id: HP:0012534
      label: Dysesthesia
  evidence:
  - reference: PMID:39258340
    reference_title: Novel Clinical Manifestation and Favorable Treatment Outcome of Cochlear Implant in a Chinese Family With Likely Pathogenic Variant of the P2RX2 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We quantitatively evaluated the pain perception ability of some members using the Pain Vision PS-2100 system, and further found an interesting clinical manifestation, that is, hyperalgesia, in heterozygotes for P2RX2 p.V60L.
    explanation: The measurement and the genotype it was made in. Quantitative rather than symptom-report, which matters for a finding this easy to dismiss.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: Reported in one human family without a sufficiently detailed denominator in the accessible abstract to estimate frequency. HP:0012534 includes Hyperalgesia as a synonym.
environmental:
- name: Occupational and recreational noise exposure
  description: Noise is a modifier of genetically determined hearing loss. Human carrier observations and controlled mouse experiments support increased susceptibility, but no genotype-specific human exposure threshold is established.
  exposure_term:
    preferred_term: exposure to sound radiation
    term:
      id: ECTO:8000044
      label: exposure to sound radiation
  evidence:
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood.
    explanation: The human evidence that noise exposure modifies the phenotype in carriers, which is what justifies curating it as an environmental entry at all.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  influences_mechanisms:
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Noise exposure is associated with worse high-frequency hearing in carriers and causes greater injury in the studied mouse models; dose, timing and molecular intermediates differ between systems.
    evidence:
    - reference: PMID:23345450
      reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood.
      explanation: Retrospective exposure-outcome association in a family, not a controlled human intervention.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
    - reference: PMID:23345450
      reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults.
      explanation: The controlled-exposure counterpart in mice, where the noise history is known rather than recalled.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  notes: Published families and selected hearing-loss cohorts establish rarity of reported cases but do not provide a population prevalence estimate. The Japanese P2RX2 candidate is confounded by mitochondrial disease and is not counted as an unequivocal causal diagnosis.
  evidence:
  - reference: PMID:25788561
    reference_title: Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study.
    explanation: An ascertained hearing-loss cohort is not a population prevalence denominator, and the P2RX2 finding itself remains uncertain.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: P2RX2
  notes: 'P2RX2 p.Val60Leu segregates in Chinese families and was independently reported in a Spanish panel cohort; p.Gly353Arg segregates in an Italian family. Functional studies characterize both alleles, with conflicting interpretations of dominant-negative action and p.Val60Leu constitutive activity.

    The Iranian report annotated c.1048T>G as p.Ter350Glu on an alternate transcript and proposed an extended protein without functional testing. ClinGen maps the same variant to NM_170682.4:c.1029T>G (p.Ile343Met) on the matched reference transcript; a general stop-loss/elongation mechanism is unsupported. That family''s proband had congenital deafness.

    The Japanese MELAS-family allele was reported as p.Asp201Tyr on a shorter transcript, equivalent to p.Asp273Tyr in the full-length receptor used for functional studies. The original c.601G>A notation is reproduced only as a published annotation, not normalized HGVS; later population work uses NM_170683.4:c.817G>T. ClinGen discounted the MELAS-confounded case. A 2025 East Asian population analysis reinterpreted p.Asp273Tyr as VUS because allele-frequency and functional/segregation evidence conflicted. Its estimated penetrance is model-based and controls lacked auditory phenotyping; it is not a verified DFNA41 penetrance estimate.

    ClinGen classified the dominant nonsyndromic hearing-loss relationship Moderate on reevaluation in September 2022. This gene-level judgment does not establish the pathogenicity of every rare P2RX2 variant.'
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  evidence:
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea.
    explanation: The gene-disease relationship and the cell types in which the receptor acts.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:24211385
    reference_title: A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL.
    explanation: The first independent replication, and its hedged wording is preserved because at that point the gene rested on two families.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:25788561
    reference_title: Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing.
    explanation: Segregation in a family also carrying the hearing-loss-associated mitochondrial variant does not establish independent P2RX2 causality.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: An additional family was reported in which hearing loss co occurred with a mitochondrial disorder, however there wasn't strong evidence in support of pathogenicity of the P2RX2 variant for this phenotype and the variant was present in gnomAD (25788561).
    explanation: ClinGen explicitly discounts this candidate-family evidence.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In summary, there is moderate evidence to support this gene-disease relationship.
    explanation: Expert gene-level assessment dated September 2022.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: The authors call this variant a stop loss variant (p.Term350Glu), but this is the HGVS on an alternate transcript of questionable biological relevance. On the MANE select transcript, this is just a standard missense variant.  # codespell:ignore mane
    explanation: Corrects the consequence annotation; this does not demonstrate the proposed protein extension.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41023131
    reference_title: Leveraging underrepresented population data improves interpretation of genetic variants associated with hearing loss.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: Of particular clinical significance, 24 of the 31 high-frequency variants were reclassified as benign or likely benign, and 1 variant, P2RX2 p.(Asp273Tyr), was reinterpreted as a VUS owing to conflicting evidence from AF and functional studies.
    explanation: Later population analysis retains uncertainty for this allele, rather than accepting it as a fully penetrant disease variant.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6842632/?report=reader
    reference_title: Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms - PMC
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: The equivalent mutation to D201Y described in the hP2X2 variant 6 (NM_01226.4) ... was introduced in the hP2X2 variant 1 (Uniprot identifier Q9UBL9-1) and rP2X2 variant 1 (Uniprot identifier P49653-1), which correspond to residues D273Y and D261Y, respectively.
    explanation: Methods explicitly relate transcript/protein numbering; the source accession spelling is retained as quoted.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:34425661
    reference_title: Identification of a Novel Stop Loss Mutation in P2RX2 Gene in an Iranian Family with Autosomal Nonsyndromic Hearing Loss.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: She was diagnosed with congenital deafness and had no dysmorphic features.
    explanation: Clinical scope of the Iranian candidate report; does not independently resolve variant pathogenicity.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Audiologic and Molecular Diagnosis
  description: Assess onset, progression, bilateral thresholds, speech understanding, family history and noise exposure. Use a multigene hearing-loss panel or genomic testing with variant interpretation; targeted family testing is appropriate once a causal variant is known. Normal childhood hearing does not exclude later loss, but childhood presentations also occur. A P2RX2 VUS, including an allele with conflicting population evidence, does not confirm DFNA41. Consider coexisting mitochondrial or other causes when clinically indicated.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A multigene hearing loss panel ... can often identify the cause of genetic hearing loss while limiting identification of pathogenic variants and variants of uncertain significance in genes that are irrelevant to the underlying phenotype
    explanation: General testing guidance, applied to the heterogeneous hearing-loss differential.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.
    explanation: Prevents gene membership or functional assays alone from being treated as a molecular diagnosis.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:31593348
    reference_title: 'Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences.
    explanation: Bilaterality and the all-frequency configuration in the same cohort.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
treatments:
- name: Hearing Conservation and Noise Avoidance
  description: Avoid repeated overexposure to loud sound and use hearing protection appropriate to exposure. This is general hearing-loss guidance with additional rationale from the observed DFNA41 noise association. Disease-specific benefit size and a safe carrier exposure limit have not been established.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: noise exposure avoidance and hearing protection
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided.
    explanation: General hearing-conservation recommendation.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood.
    explanation: The human evidence that noise exposure modifies the phenotype in carriers, which is what justifies curating it as an environmental entry at all.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: The association motivates precaution; it does not quantify an intervention effect in carriers.
- name: Genetic Counselling with Audiologic Surveillance
  description: Provide counseling on variant interpretation, variable onset/severity and the 50% probability of transmission from a heterozygous parent with a causal dominant allele. Offer appropriate testing of relatives and serial audiologic assessment, including before symptoms when a familial variant is known.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with autosomal dominant hearing loss have a 50% chance of transmitting the pathogenic variant to each child.
    explanation: Mendelian transmission probability after establishing a causal dominant allele; not a universal penetrance estimate.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Regular follow up is recommended for all individuals with genetic hearing loss
    explanation: General surveillance recommendation; tailor frequency to age and hearing trajectory.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted.
    explanation: Transmission probability does not establish age-specific penetrance or severity.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Cochlear Implantation
  description: Implantation for an ear that has reached profound loss. The reported DFNA41 experience is a single proband from a five-generation Chinese kindred carrying p.Val60Leu, with a satisfactory outcome. That family is also the one with earlier onset and worse hearing than the original DFNA41 families, so it is the part of the phenotypic range where implantation becomes relevant.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cochlear implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: Medical Device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: Cochlear Implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  evidence:
  - reference: PMID:39258340
    reference_title: Novel Clinical Manifestation and Favorable Treatment Outcome of Cochlear Implant in a Chinese Family With Likely Pathogenic Variant of the P2RX2 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The cochlear implant (CI) was also provided for the proband of profound deafness, resulting in satisfactory clinical outcomes.
    explanation: The implantation and its outcome in a molecularly confirmed DFNA41 proband.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language.
    explanation: General hearing-loss care; no DFNA41-specific efficacy estimate is inferred.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  notes: The accessible DFNA41 report describes one satisfactory outcome without quantitative speech scores in the abstract. General candidacy and rehabilitation guidance should not be converted into genotype-specific response rates.
- name: Hearing Aids and Communication Rehabilitation
  description: Individualize amplification, communication support and hearing habilitation according to measured hearing and communication needs. Use standard care even when genotype-specific outcome series are unavailable.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: Medical Device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: Hearing Aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
    reference_title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Habilitation for hearing loss includes improved access to sound through hearing aids or cochlear implants and, when desired, exposure to and teaching of American Sign Language.
    explanation: General hearing-loss care; no DFNA41-specific efficacy estimate is inferred.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Experimental Allele-Selective Genome Editing
  description: Preclinical AAV2–SaCas9 disruption of the mutant allele preserved selected auditory frequencies, cochlear cells and vestibular performance in heterozygous p.Val61Leu mice. Earlier treatment broadened preservation. A human-specific guide edited patient-derived hiPSCs. These findings do not establish human efficacy or safety; no P2RX2/DFNA41 study was returned by the ClinicalTrials.gov queries on 2026-09-23.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:41090360
    reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These findings demonstrate that AAV2–SaCas9–sgRNA-1 editing therapy provides robust and long-term preservation of hearing at specific frequencies in P2rx2V61L/+ mice.
    explanation: Measured preclinical hearing preservation, not complete normalization.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:41090360
    reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: NGS analysis revealed robust indel generation in cells edited with SaCas9-KKH/sgRNA-1, with an indel frequency of 37.9% ± 2.3%
    explanation: Human patient-derived cell editing; no auditory functional readout.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
experimental_models:
- name: Patient-derived P2RX2 p.Val60Leu hiPSC lines and their CRISPR homozygous isogenic control
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:30819013
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Non-integrative hiPSCs reprogrammed from urine-derived epithelial cells of three members of a large Chinese kindred heterozygous for P2RX2 c.178G>T (p.Val60Leu).
  description: Patient-derived heterozygous p.Val60Leu hiPSCs were generated from urine epithelial cells, and CRISPR/ssODN editing introduced the same variant into the remaining allele to create a homozygous dosage model. The 2019 paper established pluripotency and genotype without otic differentiation or channel-functional rescue.
  modeled_mechanisms:
  - target: Variant-Specific P2X2 Channel Dysfunction
    relationship: PERTURBS
    fidelity: UNKNOWN
    description: 'Establishes the p.Val60Leu allele at two dosages in a human genetic background: the patients'' own heterozygous state, and an engineered homozygote as a control for gene function.'
    limitations: Undifferentiated hiPSCs and an engineered homozygous allele-dosage control do not establish cochlear physiology or a human homozygous disease phenotype.
    evidence:
    - reference: PMID:30819013
      reference_title: Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function.
      explanation: The editing step that makes this a dosage series for the node rather than a single patient line.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:30819013
    reference_title: Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL.
    explanation: The derivation of the patient lines and the allele they carry.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: The paper labels mutant lines P2RX2+/- and P2RX2-/-, but these carry one or two missense alleles, not deletion alleles. A later study used patient-derived hiPSCs for mutation-selective editing.
- name: Human p.Val60Leu hiPSC Allele-Selective Editing
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:41090360
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: SaCas9-KKH/sgRNA-1 generated predominantly frameshifting indels in patient-derived hiPSCs. Healthy control hiPSCs showed no detected indels; targeted testing of predicted off-target sites found none. These assays establish editing feasibility within their detection limits, not cochlear efficacy or comprehensive safety.
  evidence:
  - reference: PMID:41090360
    reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: NGS analysis revealed robust indel generation in cells edited with SaCas9-KKH/sgRNA-1, with an indel frequency of 37.9% ± 2.3%
    explanation: Human patient-derived cell editing; no auditory functional readout.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  modeled_mechanisms:
  - target: Variant-Specific P2X2 Channel Dysfunction
    relationship: PERTURBS
    fidelity: UNKNOWN
    model_scale: MOLECULAR
    description: Allele-selective disruption targets the variant underlying the channel-dysfunction node.
    limitations: Editing efficiency was measured in undifferentiated cells; channel function and cochlear rescue were not measured in this human model.
    evidence:
    - reference: PMID:41090360
      reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: NGS analysis revealed robust indel generation in cells edited with SaCas9-KKH/sgRNA-1, with an indel frequency of 37.9% ± 2.3%
      explanation: Human patient-derived cell editing; no auditory functional readout.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
animal_models:
- name: P2rx2 V61L knock-in mouse
  species: Mouse
  genotype: P2rx2 p.Val61Leu/+ knock-in, corresponding to human p.Val60Leu
  publication: PMID:33791800
  description: The heterozygous mouse counterpart of human p.Val60Leu develops progressive hearing loss from postnatal day 21, with shortened inner hair cells, displaced synaptic ribbons, balance deficits and increased hot-plate sensitivity. Its time course and genetic background differ from human disease.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Inner Hair Cell and Ribbon Synapse Disorganisation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Allele-matched cochlear structural phenotype in mice, with early ribbon mislocalization and later degeneration.
    limitations: 'Human cochlear histopathology has not been demonstrated in the reviewed sources. Human onset varies, and mouse progression over months is not a direct age equivalent. Vestibular dysfunction remains a model observation: the 2019 patient-derived cell paper reports clinical vestibular testing in its methods, while the 2025 editing paper states human dysfunction has not been reported.'
    readouts:
    - name: Inner hair cell and ribbon synapse morphology
      target: Inner Hair Cell and Ribbon Synapse Disorganisation
      direction: ALTERED
      interpretation: Progressive morphological abnormality rather than an all-or-none defect, appearing over the same period as the hearing decline.
      evidence:
      - reference: PMID:33791800
        reference_title: Generation and characterization of a P2rx2 V60L mouse model for DFNA41.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses.
        explanation: The structural measurement behind this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:33791800
      reference_title: Generation and characterization of a P2rx2 V60L mouse model for DFNA41.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses.
      explanation: The structural finding in the allele-matched knock-in, stated with the authors' hedge about what it suggests.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Progressive Sensorineural Hearing Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: The allele-matched heterozygote develops progressive hearing loss.
    limitations: Mouse hearing loss begins at postnatal day 21 and reaches deafness by six months, a compressed course compared with human hearing loss that worsens over decades, so the time course is not a direct age equivalent.
    readouts:
    - name: Auditory function over time
      target: Progressive Sensorineural Hearing Impairment
      direction: DECREASED
      interpretation: Progressive hearing loss from 21 days to deafness by six months. The readout is named for function rather than for threshold because the cited sentence reports hearing loss, and a threshold moves in the opposite direction to the function it measures.
      evidence:
      - reference: PMID:33791800
        reference_title: Generation and characterization of a P2rx2 V60L mouse model for DFNA41.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old.
        explanation: The functional time course in the allele-matched heterozygote.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:33791800
      reference_title: Generation and characterization of a P2rx2 V60L mouse model for DFNA41.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old.
      explanation: Progressive hearing loss in the allele-matched heterozygote.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: P2rx2 null mouse
  species: Mouse
  genotype: P2rx2 null, homozygous
  publication: PMID:23592720
  description: The model in which the purinergic adaptation mechanism was established. Nulls lack ATP-gated conductance across the cochlear partition including ATP-gated inward current in hair cells, fail to develop the temporary threshold shift that wild-type mice develop under sustained 85 dB noise, and are more vulnerable than wild-type mice to permanent loss at 95 dB and above.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Loss of Purinergic Adaptation to Elevated Sound Levels
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Defines loss of purinergic adaptation using ABR, otoacoustic emissions, cellular currents and cochlear partition conductance.
    limitations: Homozygous deletion differs from heterozygous human missense disease. Heterozygous null mice retained temporary-threshold adaptation. Background strain and noise protocol also limit extrapolation; constitutive and altered-gating effects of missense variants are not modeled by a null.
    readouts:
    - name: Noise-induced temporary threshold shift
      target: Loss of Purinergic Adaptation to Elevated Sound Levels
      direction: ABOLISHED
      interpretation: The adaptive response to moderate sustained noise does not occur in the absence of P2X2. This is the defining measurement of the node.
      evidence:
      - reference: PMID:23592720
        reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed.
        explanation: The threshold-shift measurement in the null.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    - name: ATP-gated conductance across the cochlear partition
      target: Loss of Purinergic Adaptation to Elevated Sound Levels
      direction: ABOLISHED
      interpretation: Direct electrophysiological evidence that ATP-evoked conductance is absent; the ABR endpoint is also an electrophysiological measurement.
      evidence:
      - reference: PMID:23592720
        reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells.
        explanation: The direct conductance measurement in the null.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:23592720
      reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing.
      explanation: The conclusion this node curates, drawn from this model.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: The gene-environment interaction reproduced under controlled exposure, which is the thing human observation cannot deliver because noise history in a family is recalled rather than measured.
    limitations: Homozygous null rather than the human heterozygous state, and the exposure is a defined laboratory protocol rather than a lifetime of variable occupational and recreational sound. The direction and the interaction are reproduced; the dose is not comparable.
    readouts:
    - name: High-frequency hearing after early continuous moderate noise
      target: Noise-Exacerbated High-Frequency Hearing Impairment
      direction: DECREASED
      interpretation: Controlled early exposure produces the same high-frequency loss reported in exposed human carriers.
      evidence:
      - reference: PMID:23345450
        reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults.
        explanation: The controlled-exposure measurement.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:23592720
      reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption.
      explanation: Vulnerability to permanent noise damage measured in the same null line, which is what makes it informative for the noise-exacerbated phenotype rather than only for the adaptation node.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: P2rx2 V61L knock-in mouse treated with AAV-delivered SaCas9
  species: Mouse
  genotype: P2rx2 V61L/+ knock-in treated with AAV2 SaCas9-sgRNA targeting the mutant allele
  publication: PMID:41090360
  description: Local AAV2–SaCas9 editing of heterozygous p.Val61Leu mice preserved hearing at selected frequencies and attenuated noise-induced loss. Four-week treatment preserved low/mid-frequency responses for nine months; juvenile treatment broadened benefit. Cell survival and vestibular readouts also improved. Assays found no detectable cochlear target-site AAV integration at the tested dose, but cultured cells showed dose-dependent integration.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Noise-Exacerbated High-Frequency Hearing Impairment
    relationship: RESCUES
    fidelity: MODERATE
    description: Editing rescues the noise-susceptibility endpoint in mice. It does not directly measure restoration of ATP-dependent conductance or temporary-threshold adaptation.
    limitations: The noise challenge and treatment ages are mouse-specific. Auditory preservation was frequency-limited, not complete normalization. Human guide testing was confined to cultured cells. No detected off-target or integration event in specified assays does not establish comprehensive safety.
    readouts:
    - name: Resistance to noise-induced hearing loss after editing
      target: Noise-Exacerbated High-Frequency Hearing Impairment
      direction: RESTORED
      interpretation: Attenuation of additional ABR threshold loss after the specified noise challenge; not proof of restoration of purinergic adaptation.
      evidence:
      - reference: PMID:41090360
        reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41.
        explanation: The noise-specific rescue, and the authors' own statement that the phenotype rescued is one patients have.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:41090360
      reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41.
      explanation: The noise-specific rescue, and the authors' own statement that the phenotype rescued is one patients have.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Progressive Sensorineural Hearing Impairment
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Editing preserves auditory responses at selected frequencies, separately from the noise-susceptibility rescue.
    limitations: Auditory preservation was frequency-limited, not complete normalization, and treatment ages are mouse-specific.
    readouts:
    - name: Auditory function after editing
      target: Progressive Sensorineural Hearing Impairment
      direction: INCREASED
      interpretation: Preservation of selected-frequency auditory responses relative to untreated ears; vestibular testing was a separate endpoint.
      evidence:
      - reference: PMID:41090360
        reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: These findings demonstrate that AAV2–SaCas9–sgRNA-1 editing therapy provides robust and long-term preservation of hearing at specific frequencies in P2rx2V61L/+ mice.
        explanation: Measured preclinical hearing preservation, not complete normalization.
        directness: DIRECT
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:41090360
      reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These findings demonstrate that AAV2–SaCas9–sgRNA-1 editing therapy provides robust and long-term preservation of hearing at specific frequencies in P2rx2V61L/+ mice.
      explanation: Long-term preservation of hearing at specific frequencies after editing.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:41090360
    reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Intervention in mice at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention.
    explanation: Earlier mouse intervention broadened the range of preserved auditory frequencies; it does not imply human diagnosis must wait until adulthood.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: p2rx2 knockout zebrafish
  species: Zebrafish
  genotype: p2rx2 knockout (66 bp insertion introducing a premature TAA), homozygous
  publication: PMID:41015553
  description: A homozygous p2rx2 loss-of-function zebrafish line with a 66-base insertion introducing a premature TAA. Larval otolith-region hair-cell staining density was reduced while lateral-line counts were unchanged; adult auditory-evoked thresholds were elevated.
  genes:
  - preferred_term: P2RX2
    term:
      id: hgnc:15459
      label: P2RX2
  modeled_mechanisms:
  - target: Progressive Sensorineural Hearing Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Supports an auditory role for p2rx2 in a non-mammalian null model.
    limitations: The null genotype does not model dominant missense gating. Zebrafish lack a cochlea; the source localizes staining abnormalities to the otolith region without resolving every sensory patch. Adult thresholds were measured at one age, so progression was not established. The methods and figure legend differ in their reported sample count.
    readouts:
    - name: Auditory evoked potential threshold
      target: Progressive Sensorineural Hearing Impairment
      direction: INCREASED
      interpretation: Thresholds rose at all four frequencies tested, which is what reduced hearing sensitivity looks like when the measure is a threshold rather than a function.
      evidence:
      - reference: PMID:41015553
        reference_title: Construction and phenotypic analysis of p2rx2 knockout zebrafish lines.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: The AEP thresholds of the homozygous mutant zebrafish with the p2rx2 gene were significantly higher compared to those of the wild type zebrafish at stimulation frequencies of 600, 800, 1 000, and 2 000 Hz
        explanation: The functional measurement behind this readout, at four frequencies.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    - name: Hair cell density in the otolith region
      target: Progressive Sensorineural Hearing Impairment
      direction: DECREASED
      interpretation: Reduced otolith-region staining density at five days, not longitudinal proof of cell death or exclusive localization to the saccule.
      evidence:
      - reference: PMID:41015553
        reference_title: Construction and phenotypic analysis of p2rx2 knockout zebrafish lines.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: a marked reduction in hair cell density was evident in the otolith region of p2rx2 gene knockout zebrafish compared to controls
        explanation: The hair cell count behind this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
      - reference: PMID:41015553
        reference_title: Construction and phenotypic analysis of p2rx2 knockout zebrafish lines.
        supports: NO_EVIDENCE
        evidence_source: MODEL_ORGANISM
        snippet: no significant differences were observed in the number or arrangement of hair cells within the lateral line region between p2rx2 gene knockout zebrafish and the control group
        explanation: Unchanged lateral-line measurements delimit the phenotype; they are not positive evidence for reduced otolith density.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:41015553
      reference_title: Construction and phenotypic analysis of p2rx2 knockout zebrafish lines.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: p2rx2 deficiency caused hair cell defects in the otolith region and increased auditory thresholds across frequencies, indicating its key role in maintaining zebrafish auditory hair cell function and hearing perception
      explanation: The authors' own summary of what the line shows, which is what makes it informative for the hearing loss rather than only for the gene.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
references:
- reference: PMID:20301607
  title: Genetic Hearing Loss Overview.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
  title: Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
discussions:
- discussion_id: dfna41_carrier_noise_dose_response
  kind: KNOWLEDGE_GAP
  prompt: How much noise is too much for a P2RX2 carrier? Is there a dose below which a carrier is no worse off than a non-carrier, and does hearing conservation started before onset change the trajectory?
  attaches_to:
  - environmental#Occupational and recreational noise exposure
  - treatments#Hearing Conservation and Noise Avoidance
  - phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
  rationale: Human evidence relates recalled occupational exposure to hearing thresholds. Mouse experiments establish protocol-specific susceptibility but do not define a safe human carrier dose or show the benefit of a conservation program. A longitudinal cohort with dosimetry, audiometry and genotype-negative relatives could quantify the interaction.
  evidence:
  - reference: PMID:23345450
    reference_title: Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood.
    explanation: Observational association motivates, but does not answer, the prospective exposure-response question.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  proposed_experiments:
  - experiment_id: exp_dfna41_carrier_noise_dosimetry_cohort
    name: Longitudinal noise dosimetry in P2RX2 carriers and non-carrier relatives
    description: Enrol carriers and genotype-negative relatives from known DFNA41 kindreds, measure cumulative noise exposure by personal dosimetry rather than by questionnaire, and follow pure tone and extended high-frequency audiometry annually. Model threshold change against cumulative dose separately by genotype to estimate whether the exposure-response curve is shifted and by how much.
    would_support:
    - phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
    supporting_outcome:
    - Carriers show a steeper threshold-versus-dose slope than non-carrier relatives, with separation beginning at exposures within current occupational limits, which would justify genotype-specific exposure advice and give a number to give patients.
    would_refute:
    - phenotypes#Noise-Exacerbated High-Frequency Hearing Impairment
    refuting_outcome:
    - No association between measured exposure and excess carrier decline would weaken a genotype-specific exposure-response claim; general hearing-conservation advice would still apply.
- discussion_id: dfna41_null_versus_heterozygous_mechanism
  kind: HUMAN_MODEL_MISMATCH
  prompt: How do allele-specific channel changes in heterozygous carriers affect purinergic adaptation, and which mechanisms explain progressive loss?
  attaches_to:
  - pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
  - animal_models#P2rx2 null mouse
  rationale: 'Null-mouse physiology establishes an adaptive P2X2 pathway. Dominant missense disease is not equivalent to partial gene deletion: heterozygous null mice retained adaptation, p.Val60Leu shows assay-dependent gating abnormalities, and dominant-negative effects on wild-type P2X2 are contested. Editing improves noise-susceptibility endpoints without directly testing temporary-threshold adaptation.'
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645545/
    reference_title: ATP-gated ion channels mediate adaptation to elevated sound levels - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data indicate haplosufficiency in the development of P2X ... receptor-dependent TTS.
    explanation: Heterozygous null mice retained adaptation, preventing direct equivalence of null and dominant missense disease.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:29180951
    reference_title: 'P2X2 Dominant Deafness Mutations Have No Negative Effect on Wild-Type Isoform: Implications for Functional Rescue and in Deafness Mechanism.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These results suggest that P2X2 dominant deafness mutations do not have negative effects on WT P2X2 isoforms, and that adding additional WT P2X2 could rescue the lost channel function caused by the deafness mutations.
    explanation: Coexpression evidence challenges a universal dominant-negative interpretation; this is cellular functional rescue, not demonstrated hearing therapy.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:31636190
    reference_title: Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains.
    explanation: Gain of basal conductance coexists with loss of ATP regulation in this assay.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:41090360
    reference_title: Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss, a phenotype also observed in patients with DFNA41.
    explanation: Noise-susceptibility rescue is indirect evidence for the adaptation hypothesis, not measurement of the mechanism itself.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  proposed_experiments:
  - experiment_id: exp_dfna41_tts_in_heterozygous_knockin
    name: Temporary threshold adaptation in P2rx2 V61L heterozygous mice
    description: Compare genotype-matched and background-matched knock-in, null, heterozygous-null and wild-type mice using baseline-adjusted ABR/DPOAE noise protocols and ATP-evoked cochlear measurements. Include edited knock-in ears to test whether endpoint rescue accompanies restoration of purinergic adaptation.
    would_support:
    - pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
    supporting_outcome:
    - Reduced adaptation in knock-in mice, accompanied by correction after editing, would support the proposed link between allele dysfunction and loss of noise protection.
    would_refute:
    - pathophysiology#Loss of Purinergic Adaptation to Elevated Sound Levels
    refuting_outcome:
    - Normal adaptation despite progressive knock-in hearing loss would argue against this being the sole disease mechanism.
- discussion_id: dfna41_gene_disease_validity
  kind: KNOWLEDGE_GAP
  prompt: P2RX2 is classified Moderate rather than Definitive for dominant nonsyndromic hearing loss. What would move it, and does the strength of the mechanistic evidence make the human genetic evidence look better than it is?
  attaches_to:
  - genetic#P2RX2
  - disease#Autosomal Dominant Nonsyndromic Hearing Loss 41
  rationale: ClinGen's September 2022 evaluation scored three variants in four probands and retained Moderate validity. New segregation and population data require allele-level assessment. Functional results support biological relevance but cannot substitute for independent human genetic evidence, especially for p.Asp273Tyr with conflicting population data.
  evidence:
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
    explanation: The panel's summary judgement, in its own words.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Three missense variants that have been reported in four probands in four publications are included in this curation
    explanation: The size of the human genetic evidence base, which is the specific thing that is thin - not the mechanism.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although a new case with hearing loss (29986705) and a new knock-in mouse model with progressive hearing loss (33791800) were scored, the classification did not change (SOP Version 9).
    explanation: 'The 2022 reevaluation, which is informative about what does not move a classification: an additional case and the allele-matched knock-in this entry relies on were both scored and left it at Moderate.'
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z
    reference_title: P2RX2 / nonsyndromic genetic hearing loss (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Loss of the P2RX2 receptor in mice increases susceptibility to noise-induced hearing loss, and a significant correlation was found in a large Chinese family between noise exposure during adolescence and severity of hearing loss (PMIDs: 23345450, 33791800).'
    explanation: 'An independent restatement of the gene-environment interaction, and a more specific one than the source papers give: the human correlation is with noise exposure during adolescence and with severity, in a large family.'
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: dfna41_channel_to_cochlear_injury
  description: Allele-specific channel abnormalities may impair cochlear adaptation and contribute to cellular/synaptic injury. Null-mouse adaptation physiology and heterozygous knock-in pathology support this proposal, but the complete causal route has not been established in human carriers.
notes: Scope is Mendelian P2RX2-associated hearing loss; noise is a modifier, not the primary disease category. ClinicalTrials.gov queries for P2RX2 and DFNA41 returned no studies on 2026-09-23. The current trial search is bounded to those queries. Abstract-only clinical sources were used within their available scope; accessible primary full text informed mechanism, onset, transcript annotation and experimental limitations.
📚

References & Deep Research

References

2
PMID:20301607
Genetic Hearing Loss Overview.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1434/?report=reader
Genetic Hearing Loss Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41, P2RX2) · 2026-08-28T19:24:24Z · View source

De novo curation of DFNA41 (MONDO:0011994, P2RX2 hgnc:15459) from the stub queue. entry_type decided as DISEASE: one causal gene, no MONDO descendants, MONDO's own definition is gene-scoped, and the reported alleles converge functionally rather than diverging. Nothing in kb/ previously mentioned P2RX2. Organising point: P2X2 is not a structural hair bundle protein but part of a protective feedback system. Rising sound levels release ATP into the endolymphatic compartment, ATP opens P2X2 channels on the epithelium lining it, and the resulting conductance turns down cochlear amplifier gain - which is what a temporary threshold shift is. DFNA41 is therefore a disorder of a protective mechanism, and the noise interaction is the disease rather than a lifestyle note. The noise interaction is modelled structurally as required by issue #9904: an environmental entry bound to ECTO:8000044 (exposure to sound radiation, already cached from Noise_Induced_Hearing_Loss) with two influences_mechanisms links - EXACERBATES onto the noise-exacerbated high-frequency phenotype, and MODULATES onto the purinergic adaptation node, because sound level is the physiological input to that mechanism rather than an aggravating agent applied to it. Entry-level evidence is present, so check-environmental-evidence passes. Three animal models are curated in animal_models with modeled_mechanisms: the P2rx2 null (where the adaptation mechanism was established), the allele-matched V60L knock-in, and the AAV-SaCas9 editing rescue, which carries a RESCUES link. The editing model's limitations record that juvenile intervention broadened the rescued frequency range, so the timing that works best has no counterpart in a disease diagnosed in adults. Acted on the automated second opinion posted to #9904, which flagged ClinGen's Moderate classification. Fetched the assertion (CGGV:assertion_c1dae6b6-4ed7-4c5a-ba4e-bcfaba026be8-2022-09-21T160000.000Z) via just clingen-rebuild and used it three ways. First, a KNOWLEDGE_GAP discussion on gene-disease validity: the entry is mechanistically rich and genetically thin, and the two are easy to confuse. Second, the ClinGen narrative reads the coexpression result as a dominant-negative mechanism, so functional_impact_category was changed from LOSS_OF_FUNCTION to DOMINANT_NEGATIVE. Third, and most importantly, ClinGen reviewed the MELAS family (PMID:25788561) and did not accept it - the evidence for pathogenicity was not strong and the variant is in gnomAD. An earlier draft of this entry cited that family as a clean natural experiment supporting the gene-disease relationship. That was corrected to PARTIAL with ClinGen's reason quoted alongside, rather than either dropping it or continuing to believe it. One real defect caught by just check-snippet-grading before push: the concluding sentence of PMID:23345450 is a synthesis of human and mouse results, and was graded HUMAN_CLINICAL in the environmental and treatment blocks but MODEL_ORGANISM on an animal model link. Fixed by re-quoting the animal model link with a mouse-specific sentence from PMID:23592720 rather than by re-grading a shared quote. Also removed a Vestibular Dysfunction phenotype from an earlier draft. It was supported only by MODEL_ORGANISM evidence, which the evidence policy says should not be the sole support for a human phenotype; no vestibular testing is reported for any molecularly confirmed DFNA41 carrier. The finding is retained in the knock-in mouse limitations, where its human status is stated as untested. Evidence: 8 references cited plus one ClinGen assertion; 62/62 snippets verified against the local cache. High-frequency phenotype bound to HP:0001757 rather than HP:0005101, matching the DFNB103 entry in the same batch. Hearing amplification and cochlear implantation are not curated because no DFNA41-specific report documents either; genome editing is not curated as a treatment because it is preclinical. Deep research: falcon report run and preflighted against MONDO:0011994, verdict PASS (P2RX2=25 mentions, next gene at 2; OMIM 608224 matched on both sides). Entry curated from primary sources regardless. Validation: just validate exit 0, just validate-terms exit 0, just check-entity-refs exit 0, just check-duplicate-keys exit 0, just check-snippet-grading exit 0 after the fix.

Falcon ▸
Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41): Research Report
Edison Scientific Literature 28 citations 2026-08-28T11:38:18.063067

Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41): Research Report

Executive summary

Autosomal dominant nonsyndromic hearing loss 41 (DFNA41) is an ultrarare, postlingual, progressive sensorineural hearing disorder caused by heterozygous pathogenic variation in P2RX2, most convincingly NM_174873:c.178G>T, p.(Val60Leu). In the defining families, hearing loss was bilateral and symmetric, began at 12–20 years, initially emphasized high frequencies, and subsequently involved all frequencies. The original pedigree showed complete reported penetrance, severe thresholds of approximately 60–70 dB by age 20, and relative stabilization by the fourth decade. Occupational noise significantly worsened high-frequency hearing, making DFNA41 an unusually well-supported example of a Mendelian gene–environment interaction. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

P2X2 is an extracellular ATP-gated trimeric cation channel involved in cochlear purinergic adaptation. Val60Leu reaches the plasma membrane but abolishes ATP-evoked current in homomeric receptors and markedly impairs heteromeric-channel permeability. Mouse and cellular models implicate impaired cochlear adaptation, hair-cell and ribbon-synapse pathology, neural degeneration, and reduced resilience to acoustic stress. Current treatment remains audiological and rehabilitative. A 2025 study—beyond the requested 2023–2024 priority window—reported mutation-selective AAV2–SaCas9 editing that rescued auditory, vestibular, and noise-susceptibility phenotypes in adult mice; this remains preclinical. (yan2013mutationofthe pages 4-5, chen2021generationandcharacterization pages 2-3, wei2025singledosegenomeediting pages 2-5, wei2025singledosegenomeediting pages 1-2)

The following table summarizes the principal curation-ready findings.

domain evidence-based finding ontology/identifier suggestions evidence level/limitations
Disease identity Autosomal Dominant Nonsyndromic Hearing Loss 41 (DFNA41) is a rare Mendelian hearing-loss subtype defined from aggregated disease-level and pedigree-based human genetics data; OMIM identifier reported as 608224 (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3) OMIM: 608224; MONDO: not established from retrieved evidence; MeSH/ICD/Orphanet not confirmed in retrieved sources Human primary evidence for disease existence and mapping; some cross-database identifiers unavailable in retrieved context
Causal gene/variant The best-supported causal lesion is heterozygous P2RX2 c.178G>T, p.Val60Leu (p.V60L; NM_174873), identified in two unrelated Chinese families and absent from >7,000 controls (yan2013mutationofthe pages 2-3) P2RX2; HGNC gene symbol: P2RX2; variant: c.178G>T, p.Val60Leu Human primary evidence is strong for this variant; broader allelic spectrum was not directly resolved from retrieved full primary reports
Inheritance Inheritance is autosomal dominant with perfect cosegregation in the index pedigree, LOD score 13.3, and 100% penetrance among reported heterozygous carriers (yan2013mutationofthe pages 2-3) HP:0000006 Autosomal dominant inheritance Human pedigree evidence strong, but penetrance estimate is based on a small number of families
Core phenotype Affected individuals have bilateral, symmetrical, progressive sensorineural hearing loss, first detected at 12-20 years, ultimately involving all frequencies; severity reached about 60-70 dB by age 20 in the original family (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3) HP:0008619 Progressive hearing impairment; HP:0000407 Sensorineural hearing impairment; HP:0011453 Bilateral hearing impairment Human primary evidence; natural-history estimates remain limited because only a few families are published
Audiometric pattern/symptoms Hearing loss is typically high-frequency early, with high-frequency tinnitus reported; occupational noise exposure worsened high-frequency thresholds in mutation carriers (n=12 exposed vs n=9 unexposed, P=0.001) (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3) HP:0000366 Hearing impairment; HP:0000358 Tinnitus; HP:0001644 Dilated? not applicable; no exact HPO for noise susceptibility confirmed here Human evidence for tinnitus/noise interaction comes from small family-based comparisons
Gene-environment interaction DFNA41 shows a documented gene-environment interaction: moderate noise exposure exacerbates hearing loss in carriers, indicating increased susceptibility to noise-induced hearing loss (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3, yan2013mutationofthe pages 5-6) Exposure concept: occupational noise; phenotype concept: noise-induced hearing loss susceptibility Human evidence present but based on observational family histories rather than prospective exposure studies
Molecular function P2X2 is an extracellular ATP-gated trimeric cation channel expressed in cochlear sensory and supporting tissues; the p.V60L change abolishes ATP-evoked inward current in homomeric channels and impairs permeability in heteromeric channels (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3, mittal2016molecularstructureand pages 10-11) GO:0005230 extracellular ligand-gated ion channel activity; GO:0006811 ion transport Human/in vitro evidence strong for loss of channel function; detailed downstream pathway mapping remains incomplete
Pathomechanism The mutant receptor localizes to plasma membrane but is functionally defective, supporting a loss-of-function/gating defect rather than mislocalization; inferred disease chain is impaired purinergic cochlear adaptation and reduced protection from noise/age-related stress (yan2013mutationofthe pages 4-5, mittal2016molecularstructureand pages 10-11) GO:0007166 cell surface receptor signaling pathway; GO:0050890 cognition? not applicable; inferred cochlear homeostasis terms Mixed evidence: human cell assays plus model inference; some mechanistic steps remain inferred rather than directly proven in patients
Anatomy/cell types P2X2 expression/localization has been shown in organ of Corti, inner and outer hair cells, supporting cells, spiral ganglion neurons, and epithelial lining of the cochlea; mouse KI work also found expression in crista ampullaris (chen2021generationandcharacterization pages 2-3, yan2013mutationofthe pages 1-2) UBERON: cochlea, organ of Corti; CL: hair cell, supporting cell, spiral ganglion neuron Primarily model/histologic evidence; exact human single-cell localization was not retrieved
Diagnostics Recommended diagnosis is clinical audiologic assessment plus molecular confirmation by hearing-loss gene panel, WES, or targeted P2RX2 testing in the setting of dominant postlingual progressive SNHL and family history; temporal bone CT can be normal (yan2013mutationofthe pages 2-3, wei2025singledosegenomeediting pages 1-2) NCIT: Genetic Testing; audiology concepts: ABR/audiometry as applicable Human evidence supports genetic confirmation; no DFNA41-specific formal guideline was retrieved
Current treatment Current management is supportive: longitudinal audiologic follow-up, strict noise avoidance/protection, hearing aids, cochlear implantation when severity/function warrant it, and rehabilitation/genetic counseling (wei2025singledosegenomeediting pages 1-2, alde2023autosomaldominantnonsyndromic pages 16-17) NCIT: Hearing Aid Device; NCIT: Cochlear Implantation; NCIT: Genetic Counseling Largely inferred from standard care for dominant progressive SNHL; no DFNA41-specific interventional outcome series retrieved
Approved therapies/trials No approved molecular therapy specific to DFNA41 was identified, and no relevant registered interventional clinical trial was retrieved in the tool search (wei2025singledosegenomeediting pages 1-2) NCIT: Gene Therapy (experimental only) Evidence reflects search results, not proof of global absence; trial landscape can change rapidly
Mouse models P2rx2-null mice develop progressive hearing loss and greater noise vulnerability; the P2rx2 V61L knock-in mouse recapitulates DFNA41-related auditory disease, with hearing loss beginning at postnatal day 21 and progressing to deafness by 6 months, plus vestibular dysfunction and inner hair cell/ribbon synapse abnormalities (yan2013mutationofthe pages 1-2, chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 1-1, chen2021generationandcharacterization pages 2-3) MGI mouse P2rx2 models; phenotype terms: hearing loss, vestibular dysfunction Strong model evidence; disease onset is earlier and progression faster than in humans
Cellular models Patient-derived non-integrative hiPSCs from urine samples and CRISPR-engineered homozygous/heterozygous P2RX2 p.V60L hiPSC lines were generated as mechanistic models for hereditary hearing loss (dong2019efficientintroductionof pages 1-3) iPSC disease model; P2RX2-mutated hiPSC In vitro model only; no therapeutic efficacy in humans demonstrated
Recent translational development A 2025 preclinical study used AAV2-delivered SaCas9/sgRNA allele-specific editing in adult P2rx2V61L/+ mice, with efficient mutant-selective editing, minimal detected off-target effects, no notable AAV integration in cochlear hair cells, and rescue of long-term auditory/vestibular function plus protection from noise hypersensitivity (wei2025singledosegenomeediting pages 1-2, wei2025singledosegenomeediting pages 2-5, wei2025singledosegenomeediting pages 5-7) NCIT: CRISPR-Cas9 Genome Editing; NCIT: Adeno-Associated Virus Vector Model-only, post-2024 preclinical evidence; not yet a human therapy or clinical trial
Evidence gaps No robust disease-specific prevalence/incidence, survival, mortality, protective genetic modifiers, epigenetic biomarkers, or validated prognostic biomarkers were found in retrieved evidence (yan2013mutationofthe pages 1-2, wei2025singledosegenomeediting pages 1-2) Knowledge-base flag: data not available Important to distinguish absence of evidence from evidence of absence

Table: This table condenses the most actionable evidence on DFNA41 across identity, genetics, phenotype, mechanism, diagnosis, treatment, and models. It distinguishes human primary findings from model-based and inferred information to support knowledge-base curation.

1. Disease information

Definition

DFNA41 is a Mendelian, autosomal dominant, nonsyndromic sensorineural hearing loss. “Nonsyndromic” means that hearing impairment is the defining human clinical manifestation rather than one component of a reproducible multisystem syndrome. The disease was initially delineated in a six-generation family from Sichuan, China, and later associated with P2RX2 in that family and a second unrelated Chinese family. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

Identifiers and synonyms

  • Preferred name: Autosomal dominant nonsyndromic hearing loss 41
  • Common synonyms: DFNA41; autosomal dominant deafness 41; deafness, autosomal dominant 41; P2RX2-related dominant hearing loss
  • OMIM: 608224 (DFNA41/deafness, autosomal dominant 41)
  • Causal gene: P2RX2, purinergic receptor P2X 2
  • Locus: chromosome 12q24–qter; the refined original interval was hg19 chr12:129,051,849–133,851,895. (yan2013mutationofthe pages 1-2)
  • MONDO: A disease-specific MONDO identifier could not be verified from the retrieved evidence. Use the verified OMIM identifier and parent concepts such as hereditary nonsyndromic sensorineural hearing loss until an ontology release confirms a dedicated MONDO record.
  • Orphanet: No disease-specific Orphanet identifier was verified.
  • ICD-10/ICD-11: No DFNA41-specific billing code exists in the retrieved evidence; code the manifest bilateral sensorineural hearing loss and genetic etiology as permitted locally.
  • MeSH: No uniquely specific DFNA41 heading was verified; broader concepts include Hearing Loss, Sensorineural and Hearing Loss, Hereditary.

The evidence is principally aggregated disease-level information derived from published family studies, not routine EHR-derived patient-level surveillance. The foundational evidence nevertheless consists of individual family members’ genotypes, audiograms, exposure histories, and clinical examinations. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The strongest established cause is a germline heterozygous P2RX2 missense variant, c.178G>T, p.(Val60Leu). It cosegregated perfectly with hearing loss in the index pedigree, yielding a LOD score of 13.3, and penetrance among reported heterozygotes was 100%. Screening 65 additional dominant nonsyndromic hearing-loss families identified the same variant in another unrelated Chinese family. It was absent from 7,000 controls—4,300 European-ancestry, 2,200 African-American, and 500 Chinese individuals—giving historical estimated frequencies below 0.0001 in the mixed sample and below 0.001 in the Chinese sample. (yan2013mutationofthe pages 2-3)

This variant is germline, not somatic. Published reports describe additional P2RX2 variants in hearing-loss families, including an Italian family and an Iranian stop-loss report, but the retrieved full-text evidence was insufficient to curate their exact HGVS notation, segregation, modern ClinVar assertions, or functional strength confidently. Consequently, Val60Leu should remain the reference, best-validated DFNA41 allele, and other alleles should be evaluated individually rather than assumed equivalent. (mittal2016molecularstructureand pages 10-11, wei2025singledosegenomeediting pages 18-18)

Risk factors

  • Genetic: A heterozygous pathogenic P2RX2 allele; an affected parent or other vertical family history.
  • Age: Thresholds worsen with age, particularly from adolescence through early/middle adulthood.
  • Noise: Occupational/recreational acoustic exposure is the best-supported modifiable factor. In the original family, noise-exposed carriers (n=12) had poorer 2–8-kHz thresholds than unexposed carriers (n=9; P=0.001). Exposures in construction trades during ages 12–25 were specifically reported. (yan2013mutationofthe pages 3-4, yan2013mutationofthe pages 2-3)
  • Sex: No sex-specific difference has been established.
  • Tobacco, alcohol, diet, exercise, pollution, infection, or ototoxic drugs: No DFNA41-specific risk estimates are available. General cochlear-risk counseling remains reasonable but must not be represented as disease-specific evidence.

Protective factors

No protective P2RX2 alleles, validated modifier genes, diets, drugs, or prophylactic agents have been demonstrated. Practical acoustic protection—avoiding hazardous exposure, reducing duration/intensity, and correctly using hearing protection—is biologically compelling because noise is a demonstrated phenotype modifier, although no prospective prevention trial has quantified benefit in DFNA41.

Causal gene–environment chain

P2RX2 Val60Leu → impaired ATP-gated cochlear channel activity → reduced purinergic adaptation during elevated sound → excessive acoustic stress and impaired ionic/homeostatic response → accelerated high-frequency threshold elevation and cochlear cellular injury. The human exposure association and mouse noise challenge jointly support this chain. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 4-5, yan2013mutationofthe pages 5-6)

3. Phenotypes

Core human phenotype

Phenotype Characteristics Suggested HPO annotation
Sensorineural hearing impairment Defining manifestation; moderate-to-severe or severe with progression HP:0000407 Sensorineural hearing impairment
Bilateral/symmetric hearing impairment Bilateral and symmetrical in reported families HP:0011453 Bilateral hearing impairment; symmetry may require a qualifier
Progressive hearing impairment Chronic progression from adolescence, often stabilizing by the fourth decade HP:0008619 Progressive hearing impairment
Postlingual onset Usually 12–20 years in the defining families HP:0008504 Late-onset sensorineural hearing impairment or appropriate onset modifier
High-frequency hearing impairment Early sloping/high-frequency predominance, eventually all frequencies HP:0005101 High-frequency hearing impairment
Tinnitus Generally high-frequency tinnitus in affected members HP:0000360 Tinnitus
Increased noise susceptibility Acoustic exposure significantly worsens high-frequency thresholds Use exposure annotation plus noise-induced hearing-loss susceptibility; no exact HPO term was verified

The original report stated: “Audiologic evaluation of family members revealed bilateral and symmetrical sensorineural hearing loss, with age at onset ranging from 12 y to 20 y, generally accompanied by high-frequency tinnitus.” Hearing loss ultimately involved all frequencies. In the index family, it was severe—approximately 60–70 dB—by age 20, with relatively little subsequent progression; pooled thresholds declined until the fourth decade and then remained approximately stable. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

Vestibular phenotype

Vestibular dysfunction is prominent in the Val61Leu knock-in mouse, but a consistent vestibular disorder has not been established in the defining human families. It should therefore be recorded as a model phenotype, not a core human DFNA41 feature. (chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 1-1)

Frequency and quality of life

Penetrance was 100% in the reported index pedigree, but exact frequencies of tinnitus, individual audiometric configurations, and vestibular symptoms are not robustly estimable from the few published families. No DFNA41-specific EQ-5D, SF-36, PROMIS, speech-recognition, education, employment, or caregiver-burden study was identified. Likely effects include impaired communication, speech understanding in noise, school/work participation, tinnitus burden, and eventual hearing-device dependence; these are clinically reasonable consequences of progressive sensorineural loss, not measured DFNA41-specific outcomes.

4. Genetic and molecular information

Gene and protein

  • Gene: P2RX2
  • Protein: P2X purinoceptor 2/P2X2 receptor
  • Reference transcript used in the foundational report: NM_174873
  • Reference protein cited in the mouse study: NP_733782
  • Variant: c.178G>T, p.(Val60Leu)
  • Genomic coordinate in the original report: hg19 chr12:133,196,029G>T
  • Variant class: missense SNV
  • Origin: constitutional/germline
  • Inheritance: autosomal dominant
  • Population frequency: absent from the historical 7,000-control dataset; contemporary gnomAD frequency was not independently verified here. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3, chen2021generationandcharacterization pages 2-3)

The Val60 residue is highly conserved across vertebrates. The variant has strong pathogenic evidence: cosegregation, two unrelated families with concordant phenotype, extreme rarity, functional loss, and matching animal phenotypes. A clinical laboratory should nevertheless apply current ACMG/AMP hearing-loss specifications and report its current ClinVar classification/accession rather than copy a historical label uncritically.

Functional consequence

Wild-type P2X2 channels responded to ATP with inward current; 1 mM ATP produced a mean current of 2.17 ± 0.46 nA in wild-type-transfected HEK293 cells (n=16), whereas Val60Leu-transfected cells showed no response (n=15). Mutant channels also lacked ATP-stimulated FM1-43 permeability. Coexpression of wild-type and mutant subunits—modeling heterozygosity—reduced ATP-activated permeability by approximately 60%. Both proteins targeted the plasma membrane, arguing for defective gating/channel function rather than simple trafficking failure. (yan2013mutationofthe pages 3-4, yan2013mutationofthe pages 2-3)

The literature uses both “loss of function” and, in a later editing paper, “gain-of-function mutation.” The direct electrophysiology supports loss of ATP-activated channel function with a dominant interfering effect in heteromeric trimers. “Dominant-negative” is mechanistically plausible but should be used cautiously unless a variant-specific clinical laboratory or functional study explicitly adopts that classification. (yan2013mutationofthe pages 4-5, wei2025singledosegenomeediting pages 1-2)

Other genomic and regulatory information

No recurrent CNV, translocation, inversion, aneuploidy, repeat expansion, mitochondrial lesion, somatic mosaicism, or epigenetic signature is established as the cause of DFNA41. No validated modifier gene, methylation biomarker, chromatin abnormality, or disease-specific transcriptomic, proteomic, metabolomic, or lipidomic signature was identified.

5. Environmental information

Noise is the only non-genetic exposure with direct DFNA41-specific human evidence. Affected carriers may be harmed by exposure levels tolerated by noncarriers, and the original authors discussed susceptibility even around occupational levels conventionally regarded as acceptable. (yan2013mutationofthe pages 5-6)

There is no evidence that infection causes or triggers DFNA41. Smoking, alcohol, diet, physical activity, radiation, air pollution, and occupational chemicals have not been studied specifically. Ototoxic medications may independently injure hearing, but a P2RX2-specific pharmacogenetic interaction has not been demonstrated.

6. Mechanism and pathophysiology

Upstream molecular defect

P2X2 is a trimeric, extracellular ATP-gated nonselective cation channel. In the inner ear it is implicated in sound-transduction regulation, auditory neurotransmission, outer-hair-cell electromotility, gap-junction-associated homeostasis, and potassium recycling. Extracellular ATP released during acoustic stress activates P2 receptors in sensory, supporting, and neural tissues, reducing cochlear sensitivity and contributing to adaptation. (yan2013mutationofthe pages 1-2, mittal2016molecularstructureand pages 10-11)

Causal chain

  1. Germline P2RX2 Val60Leu alters a conserved extracellular/transmembrane-coupled gating region.
  2. Mutant subunits reach the membrane but fail to generate normal ATP-evoked current; mixed wild-type/mutant trimers have reduced permeability.
  3. Cochlear sensory and supporting cells cannot mount normal ATP-dependent adaptation and ionic shunting during sustained sound.
  4. Repeated physiological, age-related, and acoustic stress leads to impaired hair-cell/synaptic function.
  5. Model pathology includes abnormal inner-hair-cell morphology, disrupted ribbon-synapse distribution, hair/supporting-cell loss, and spiral-ganglion-neuron loss.
  6. Clinically this produces progressive, initially high-frequency sensorineural hearing loss, accelerated by noise. (yan2013mutationofthe pages 4-5, chen2021generationandcharacterization pages 2-3)

Suggested ontology terms

  • GO molecular function: extracellular ATP-gated cation channel activity; ligand-gated ion-channel activity; purinergic nucleotide receptor activity.
  • GO biological process: ion transmembrane transport; cellular response to ATP; potassium-ion homeostasis; sensory perception of sound; auditory receptor-cell development; chemical synaptic transmission; response to acoustic stimulus.
  • GO cellular component: plasma membrane; stereocilium membrane where supported; Golgi apparatus; mitochondrion; presynaptic ribbon/synaptic region.
  • Cell Ontology: inner hair cell; outer hair cell; cochlear supporting cell; spiral ganglion neuron; vestibular hair cell.

The organelle localization reported in mouse fibroblasts—plasma membrane, Golgi, and mitochondria—does not by itself establish mitochondrial dysfunction as a human disease mechanism. Likewise, inflammation, apoptosis, oxidative stress, and immune activation are plausible downstream pathways in acoustic injury but have not been specifically demonstrated as primary DFNA41 mechanisms.

Molecular profiling and advanced technologies

No DFNA41 single-cell atlas, spatial-transcriptomic dataset, unbiased proteome/metabolome, or multi-omics patient cohort was found. Available advanced platforms are targeted: electrophysiology, immunolocalization, patient-derived hiPSCs, CRISPR-engineered isogenic lines, targeted sequencing, and in-vivo allele editing. Patient-derived nonintegrating hiPSCs were generated from urine samples of three family members, and CRISPR plus single-stranded donor oligonucleotides generated homozygous isogenic mutant cells. These are mechanistic models, not diagnostic assays or therapies. (dong2019efficientintroductionof pages 1-3)

7. Anatomical structures affected

The primary organ is the inner ear, specifically the cochlea. Relevant structures include the organ of Corti, inner and outer hair cells, supporting epithelium, spiral ganglion and auditory nerve pathway, lateral-wall homeostatic system, and ribbon synapses. P2X2 expression in the knock-in study was strong in the organ of Corti, spiral ganglion, and crista ampullaris; within the cochlea it was present in inner/outer hair cells, supporting cells, and spiral ganglion neurons. (chen2021generationandcharacterization pages 2-3)

Suggested anatomy annotations include UBERON: cochlea, organ of Corti, inner ear, spiral ganglion, auditory hair cell, and crista ampullaris. The human hearing loss is bilateral and symmetric. Temporal-bone CT in one affected person was normal, consistent with a molecular/cellular rather than gross malformation disorder. No secondary systemic-organ involvement has been established. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)

8. Temporal development

  • Onset: Insidious, postlingual, usually 12–20 years in the original families.
  • Early stage: High-frequency threshold elevation and tinnitus; speech understanding in noise may deteriorate before broad-frequency disability.
  • Intermediate stage: Progressive involvement of additional frequencies; approximately 60–70-dB severity by age 20 in the index pedigree.
  • Later stage: Mean thresholds declined until approximately the fourth decade and then were comparatively stable, although individual trajectories and noise exposure varied.
  • Course: Chronic/lifelong; neither episodic nor relapsing-remitting.
  • Remission: No spontaneous or treatment-induced biological remission documented.
  • Critical period: Early identification, before extensive cochlear degeneration or hazardous noise exposure, is the rational intervention window. Mouse editing produced broader frequency rescue when delivered earlier, but the human window is unknown. (yan2013mutationofthe pages 2-3, wei2025singledosegenomeediting pages 1-2)

9. Inheritance and population

DFNA41 is autosomal dominant: each child of a heterozygous affected individual has a theoretical 50% probability of inheriting the familial variant. Reported penetrance for Val60Leu was 100% in the index family, but this estimate may not generalize to every P2RX2 allele or age. Expressivity varies with age and noise exposure. No anticipation, repeat expansion, parent-of-origin effect, or established germline mosaicism has been reported. (yan2013mutationofthe pages 2-3)

Prevalence and incidence per 100,000 are unknown. The small number of reported families and absence from 7,000 historical controls indicate an ultrarare disorder. The reference Val60Leu allele was initially found in two Chinese families; this does not prove a founder effect because shared ancestry/haplotype evidence was not established. Other population reports suggest allelic and geographic expansion, but robust ancestry-specific frequencies are unavailable. No sex bias is expected for an autosomal disorder and none has been demonstrated. Consanguinity is not etiologically relevant to the dominant inheritance pattern, although it may coexist incidentally.

10. Diagnostics

Clinical evaluation

Diagnosis requires:

  1. Personal and three-generation family history, including age at onset, tinnitus, vestibular symptoms, occupational/recreational noise, and ototoxic exposure.
  2. Otoscopy and middle-ear assessment to exclude conductive disease.
  3. Bilateral pure-tone audiometry, bone conduction, speech reception/recognition, and serial testing to document progression.
  4. Tympanometry; otoacoustic emissions and auditory brainstem responses when age, reliability, or auditory-neuropathy differential warrants them.
  5. Vestibular examination/testing only if symptoms are present or for detailed phenotyping.
  6. Imaging when cochlear implantation, asymmetry, neurologic signs, or another structural disorder is suspected—not as a molecular confirmation test. One affected carrier had normal temporal bones on CT. (yan2013mutationofthe pages 2-3)

No blood chemistry, urine assay, enzyme assay, biopsy, histopathology, circulating protein, metabolite, or imaging biomarker is diagnostic.

Genetic testing

A comprehensive hearing-loss NGS panel containing P2RX2 is generally the most efficient first molecular test. Sequence analysis must detect SNVs and small indels; exon-level CNV analysis is useful for the broader differential, although no recurrent P2RX2 CNV is established. Familial Val60Leu can be confirmed by targeted Sanger sequencing. WES or WGS is appropriate when a panel is negative, phenotype is atypical, structural/noncoding variation is suspected, or reanalysis is anticipated. WGS offers more uniform coverage and noncoding/structural-variant detection but has no proven DFNA41-specific yield advantage.

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine tests for classic DFNA41; deploy them only when the phenotype or family history suggests another diagnosis. RNA sequencing is research-level because no validated P2RX2 splicing biomarker exists.

Pathogenic/likely pathogenic results should be confirmed and segregated in relatives. A VUS must not establish diagnosis or direct predictive testing without additional evidence.

Differential diagnosis

The principal differential includes other autosomal dominant progressive nonsyndromic hearing losses—particularly KCNQ4/DFNA2, WFS1/DFNA6/14/38, TECTA/DFNA8/12, ACTG1/DFNA20/26, POU4F3/DFNA15, MYO6/DFNA22, EYA4/DFNA10—and acquired noise-induced, ototoxic, infectious, autoimmune, structural, and age-related hearing loss. The combination of adolescent onset, bilateral symmetric progression, vertical inheritance, and disproportionate noise susceptibility suggests but does not uniquely identify DFNA41. A 2023 review emphasized that dominant nonsyndromic loss is usually bilateral, postlingual, high-frequency, and progressive, underscoring the need for molecular rather than phenotype-only diagnosis. (alde2023autosomaldominantnonsyndromic pages 16-17)

Screening

Universal newborn physiologic hearing screening may be normal because DFNA41 is commonly postlingual. The key strategy is cascade genetic testing after identifying a familial pathogenic variant, followed by baseline and serial audiometry in carriers. Predictive testing of minors can be clinically useful because noise avoidance and auditory surveillance are actionable during childhood/adolescence.

11. Outcome and prognosis

DFNA41 is not known to reduce survival or life expectancy, and disease-specific mortality is not reported. Morbidity is auditory: progressive communication disability, tinnitus, reduced speech understanding—especially in noise—and possible eventual dependence on amplification or implantation. Human vestibular disability is insufficiently characterized.

Untreated sensorineural loss does not biologically recover. Hearing aids and cochlear implants can improve function but do not correct the underlying channel defect. Prognosis depends on baseline thresholds, age, rate of progression, speech recognition, acoustic exposure, and timely rehabilitation. The familial P2RX2 genotype predicts susceptibility but is not a validated quantitative prognostic biomarker.

12. Treatment

Current standard management

There is no approved DFNA41-specific pharmacotherapy and no established P2RX2-directed pharmacogenomic algorithm. Management is individualized:

  • Regular audiology, with shorter intervals during childhood, after threshold change, or after major noise exposure.
  • Hearing aids when thresholds or communication needs warrant them.
  • Remote microphones, classroom/workplace accommodations, captioning, and auditory/speech-language rehabilitation.
  • Tinnitus counseling and evidence-based tinnitus management.
  • Cochlear-implant assessment for severe-to-profound loss with inadequate aided speech understanding.
  • Genetic counseling and cascade testing.
  • Strict acoustic-risk reduction.

Suggested NCIT concepts include Hearing Aid Device, Cochlear Implantation, Auditory Rehabilitation, Speech Therapy, Genetic Counseling, and Genetic Testing. No DFNA41-specific response rate or adverse-event dataset exists; outcomes should be drawn from the applicable device and rehabilitation population rather than attributed to this genotype.

Experimental genome editing

A 2025 JCI study used local round-window-membrane injection plus canal fenestration to deliver AAV2–Staphylococcus aureus Cas9–sgRNA into adult P2rx2Val61Leu/+ mice. The strategy disrupted the mutant allele while preserving wild type. In primary cells, SaCas9–sgRNA-1 produced 75.01% ± 4.55% mutant-allele indels versus 0.45% ± 0.39% on the wild-type allele; 85.1% of indels were frameshifting. In vivo whole-cochlea indels were 2.62% ± 0.64%, while mutant-transcript and isolated-hair-cell analyses indicated approximately 28% editing of P2rx2-expressing cells and 26.96% ± 4.2% mutant-allele editing in isolated hair cells. No CIRCLE-seq off-target site beyond the target was found in the reported cell assay, and no notable AAV integration was detected at the cochlear target under the therapeutic conditions. (wei2025singledosegenomeediting pages 5-7, wei2025singledosegenomeediting pages 2-5)

The abstract states that editing “effectively restores long-term auditory and vestibular function” and protects mice from the heightened noise-induced phenotype. Juvenile intervention rescued a broader frequency range, and a human-Val60Leu-specific guide was identified. Nevertheless, this is mouse evidence: inner-ear surgical delivery, durability, immune response, off-target detection sensitivity, large rearrangements, human cochlear coverage, and allele specificity require further validation. No DFNA41 human interventional trial or NCT identifier was found in the ClinicalTrials.gov search. (wei2025singledosegenomeediting pages 1-2)

13. Prevention

Primary prevention

The inherited variant cannot presently be prevented in an individual after conception. For carriers, the most important modifiable action is prevention of avoidable acoustic injury: engineering controls, lower volume, shorter exposure, distance from sound sources, correctly fitted hearing protection, and occupational-health review. Avoid unnecessary ototoxic exposure and monitor hearing when an ototoxic drug is medically essential, although no P2RX2-specific drug interaction has been shown.

Secondary prevention

  • Cascade testing of at-risk relatives.
  • Baseline audiometry before expected onset.
  • Periodic surveillance to detect subtle high-frequency loss.
  • Early amplification and educational/work accommodations.
  • Prompt reassessment after tinnitus, perceived decline, or significant noise exposure.

Tertiary prevention

Appropriate hearing technology, communication rehabilitation, tinnitus care, fall/vestibular assessment when symptomatic, and psychosocial/occupational accommodations reduce disability.

Reproductive counseling

Counsel regarding the 50% transmission probability, variable severity and noise-modified expressivity, natural conception with prenatal diagnosis, and IVF with PGT-M where legally and ethically available. Carrier screening is not the appropriate concept for an autosomal dominant disorder; targeted predictive testing of relatives is more relevant. There is no applicable vaccine, anti-infective prophylaxis, or population-wide DFNA41 screening program.

14. Other species and natural disease

P2rx2 is evolutionarily conserved in vertebrates, and Val60/61 lies in a highly conserved region. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). A naturally occurring companion-animal, livestock, or wildlife disorder confidently homologous to human DFNA41 was not identified. There is no zoonotic or cross-species transmission because this is an inherited channelopathy, not an infection.

Comparative work demonstrates conservation of cochlear P2X2-mediated acoustic adaptation, but species differ in cochlear maturation and disease timing. Veterinary breed/VBO annotations are therefore unavailable.

15. Model organisms and experimental systems

P2rx2-null mouse

P2rx2-knockout mice develop progressive hearing loss, particularly in the high-frequency basal cochlea, and exaggerated noise-induced threshold shifts. At advanced age they show degeneration involving hair cells, supporting cells, and spiral ganglion neurons. After early moderate noise exposure, knockout mice had approximately 13-dB greater thresholds at 20–36 kHz than controls. This model establishes the protective function of P2X2 but models complete loss, not the exact heterozygous human allele. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 4-5)

P2rx2Val61Leu knock-in mouse

The mouse homolog of human Val60 is Val61. Heterozygous knock-in mice developed hearing loss by postnatal day 21 and deafness by approximately six months, accompanied by vestibular dysfunction and progressive inner-hair-cell and ribbon-synapse abnormalities. Expression was seen in inner/outer hair cells, supporting cells, spiral ganglion neurons, and crista ampullaris. This is the principal allele-specific model and the platform used for genome editing. Its limitation is substantially earlier and faster progression than the usual human 12–20-year onset. (chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 1-1, chen2021generationandcharacterization pages 2-3)

Cellular models

  • HEK293 cells: ATP-current electrophysiology.
  • MDCK-II cells: ATP-dependent FM1-43 permeability.
  • Rat organ-of-Corti cultures: receptor targeting/localization.
  • Patient-derived hiPSCs and CRISPR-generated isogenic mutant hiPSCs: human genetic background and differentiation platform.
  • HEI-OC1 cochlear cells and mouse fibroblasts: allele-specific editor screening and off-target assessment. (yan2013mutationofthe pages 2-3, dong2019efficientintroductionof pages 1-3, wei2025singledosegenomeediting pages 2-5)

The hiPSCs were described as “good models to investigate the pathological mechanisms,” but they do not reproduce the mature cochlear architecture, tonotopy, acoustic mechanics, or lifelong exposure history. Organoids, single-cell profiling, and spatial assays could help bridge that gap.

Evidence hierarchy, recent developments, and gaps

The decisive human evidence remains the 2013 genetic-functional study; no 2023–2024 primary study materially redefined the DFNA41 phenotype or causal allele in the retrieved corpus. The most relevant recent review context is the 2023 synthesis of autosomal dominant nonsyndromic hearing loss, while the major disease-specific translational advance was published in 2025, after submission in October 2024. (alde2023autosomaldominantnonsyndromic pages 16-17, wei2025singledosegenomeediting pages 1-2)

Key unresolved areas are disease prevalence, complete allelic spectrum, contemporary ClinVar/gnomAD curation for each allele, prospective natural history, speech-recognition and quality-of-life outcomes, human vestibular involvement, modifiers other than noise, biomarkers, optimal surveillance intervals, genotype-specific implant outcomes, and human safety/efficacy of allele editing.

Principal references

  1. Yan D, et al. Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise. PNAS. Published February 5, 2013;110:2228–2233. DOI/URL: https://doi.org/10.1073/pnas.1222285110. The abstract directly states that Val60Leu “abolishes two hallmark features” of P2X2 receptors and that noise worsened hearing in heterozygous relatives. (yan2013mutationofthe pages 1-2, yan2013mutationofthe pages 2-3)
  2. Housley GD, et al. ATP-gated ion channels mediate adaptation to elevated sound levels. PNAS. Published 2013;110:7494–7499. DOI/URL: https://doi.org/10.1073/pnas.1222295110. This supplies complementary model evidence for P2X2-mediated acoustic adaptation. (yan2013mutationofthe pages 1-2)
  3. Dong Y, et al. Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides. J Int Med Res. Published 2019;47:1717–1730. DOI/URL: https://doi.org/10.1177/0300060519829990. (dong2019efficientintroductionof pages 1-3)
  4. Chen X, et al. Generation and characterization of a P2rx2 V60L mouse model for DFNA41. Human Molecular Genetics. Published March 2021;30:985–995. DOI/URL: https://doi.org/10.1093/hmg/ddab077. The abstract reports hearing loss at day 21, deafness by six months, vestibular dysfunction, and ribbon-synapse abnormalities. (chen2021generationandcharacterization pages 1-2, chen2021generationandcharacterization pages 2-3)
  5. Vlajkovic SM, Thorne PR. Purinergic Signalling in the Cochlea. International Journal of Molecular Sciences. Published November 2022;23:14874. DOI/URL: https://doi.org/10.3390/ijms232314874. Review evidence for cochlear ATP signaling and acoustic adaptation.
  6. Aldè M, et al. Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review. Biomedicines. Published June 2023;11:1616. DOI/URL: https://doi.org/10.3390/biomedicines11061616. (alde2023autosomaldominantnonsyndromic pages 16-17)
  7. Wei W, et al. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with DFNA41 deafness. Journal of Clinical Investigation. Published August 14, 2025;135:e187872. DOI/URL: https://doi.org/10.1172/JCI187872. Model-only therapeutic evidence; no human efficacy is established. (wei2025singledosegenomeediting pages 5-7, wei2025singledosegenomeediting pages 2-5, wei2025singledosegenomeediting pages 1-2)

References

  1. (yan2013mutationofthe pages 1-2): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  2. (yan2013mutationofthe pages 2-3): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  3. (yan2013mutationofthe pages 4-5): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  4. (chen2021generationandcharacterization pages 2-3): Xiaoya Chen, Clemer Abad, Zheng-yi Chen, Juan I Young, Channabasavaiah B Gurumurthy, Katherina Walz, and Xue Zhong Liu. Generation and characterization of a p2rx2 v60l mouse model for dfna41. Human molecular genetics, 30:985-995, Mar 2021. URL: https://doi.org/10.1093/hmg/ddab077, doi:10.1093/hmg/ddab077. This article has 10 citations and is from a domain leading peer-reviewed journal.

  5. (wei2025singledosegenomeediting pages 2-5): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  6. (wei2025singledosegenomeediting pages 1-2): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  7. (yan2013mutationofthe pages 5-6): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

  8. (mittal2016molecularstructureand pages 10-11): Rahul Mittal, Brandon Chan, M'hamed Grati, Jeenu Mittal, Kunal Patel, Luca H. Debs, Amit P. Patel, Denise Yan, Prem Chapagain, and Xue Zhong Liu. Molecular structure and regulation of p2x receptors with a special emphasis on the role of p2x2 in the auditory system. Journal of Cellular Physiology, 231:1656-1670, Aug 2016. URL: https://doi.org/10.1002/jcp.25274, doi:10.1002/jcp.25274. This article has 26 citations and is from a peer-reviewed journal.

  9. (alde2023autosomaldominantnonsyndromic pages 16-17): Mirko Aldè, Giovanna Cantarella, Diego Zanetti, Lorenzo Pignataro, Ignazio La Mantia, Luigi Maiolino, Salvatore Ferlito, Paola Di Mauro, Salvatore Cocuzza, Jérôme René Lechien, Giannicola Iannella, Francois Simon, and Antonino Maniaci. Autosomal dominant non-syndromic hearing loss (dfna): a comprehensive narrative review. Biomedicines, 11:1616, Jun 2023. URL: https://doi.org/10.3390/biomedicines11061616, doi:10.3390/biomedicines11061616. This article has 65 citations.

  10. (chen2021generationandcharacterization pages 1-2): Xiaoya Chen, Clemer Abad, Zheng-yi Chen, Juan I Young, Channabasavaiah B Gurumurthy, Katherina Walz, and Xue Zhong Liu. Generation and characterization of a p2rx2 v60l mouse model for dfna41. Human molecular genetics, 30:985-995, Mar 2021. URL: https://doi.org/10.1093/hmg/ddab077, doi:10.1093/hmg/ddab077. This article has 10 citations and is from a domain leading peer-reviewed journal.

  11. (chen2021generationandcharacterization pages 1-1): Xiaoya Chen, Clemer Abad, Zheng-yi Chen, Juan I Young, Channabasavaiah B Gurumurthy, Katherina Walz, and Xue Zhong Liu. Generation and characterization of a p2rx2 v60l mouse model for dfna41. Human molecular genetics, 30:985-995, Mar 2021. URL: https://doi.org/10.1093/hmg/ddab077, doi:10.1093/hmg/ddab077. This article has 10 citations and is from a domain leading peer-reviewed journal.

  12. (dong2019efficientintroductionof pages 1-3): Yunpeng Dong, Tao Peng, Weijing Wu, Donghui Tan, Xuezhong Liu, and Dinghua Xie. Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using crispr/cas9 and single-stranded donor oligonucleotides. The Journal of International Medical Research, 47:1717-1730, Feb 2019. URL: https://doi.org/10.1177/0300060519829990, doi:10.1177/0300060519829990. This article has 12 citations.

  13. (wei2025singledosegenomeediting pages 5-7): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  14. (wei2025singledosegenomeediting pages 18-18): Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, and Zheng-Yi Chen. Single-dose genome editing therapy rescues auditory and vestibular functions in adult mice with dfna41 deafness. Journal of Clinical Investigation, Aug 2025. URL: https://doi.org/10.1172/jci187872, doi:10.1172/jci187872. This article has 5 citations and is from a highest quality peer-reviewed journal.

  15. (yan2013mutationofthe pages 3-4): Denise Yan, Yan Zhu, Tom Walsh, Dinghua Xie, Huijun Yuan, Asli Sirmaci, Taro Fujikawa, Ann Chi Yan Wong, Tze L. Loh, Lilin Du, M’hamed Grati, Srdjan M. Vlajkovic, Susan Blanton, Allen F. Ryan, Zheng-Yi Chen, Peter R. Thorne, Bechara Kachar, Mustafa Tekin, Hong-Bo Zhao, Gary D. Housley, Mary-Claire King, and Xue Z. Liu. Mutation of the atp-gated p2x2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proceedings of the National Academy of Sciences, 110:2228-2233, Jan 2013. URL: https://doi.org/10.1073/pnas.1222285110, doi:10.1073/pnas.1222285110. This article has 196 citations and is from a highest quality peer-reviewed journal.

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